Hubbry Logo
DefensinDefensinMain
Open search
Defensin
Community hub
Defensin
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Defensin
Defensin
Defensin
View on Wikipedia
from Wikipedia
Defensin
Example defensins with alpha helix in red, beta strands in blue, disulphide bonds in yellow (PDB: 1MR4, 2KOZ, 1FJN, 2LXZ, 1IJV, 2RNG​)
Identifiers
SymbolDefensin
Pfam clanCL0075
OPM superfamily54
OPM protein6cs9

Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate[1] and invertebrate[2] animals, plants,[3][4] and fungi.[5] They are host defense peptides, with members displaying either direct antimicrobial activity, immune signaling activities, or both. They are variously active against bacteria, fungi and many enveloped and nonenveloped viruses. They are typically 18-45 amino acids in length, with three or four highly conserved disulphide bonds.

In animals, they are produced by cells of the innate immune system and epithelial cells, whereas in plants and fungi they are produced by a wide variety of tissues. An organism usually produces many different defensins, some of which are stored inside the cells (e.g. in neutrophil granulocytes to kill phagocytosed bacteria), and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of the microbial cell membrane to metabolic disruption.

Varieties

[edit]
Characteristic disulphide linkages
Trans-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to two different secondary structure elements (motif = CC). On the right, an example structure (PDB: 1IJV​).
Cis-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to the same alpha helix (motif = CxC...CxxxC). On the right, an example structure (PDB: 1MRR4​).

The name 'defensin' was coined in the mid-1980s, though the proteins have been called 'Cationic Antimicrobial Proteins,' 'Neutrophil peptides,' 'Gamma thionins' amongst others.[6]

Proteins called 'defensins' are not all evolutionarily related to one another.[7] Instead fall into two broad superfamilies, each of which contains multiple families.[7][8] One superfamily, the trans-defensins, contains the defensins found in humans and other vertebrates,[9][10] as well as some invertebrates.[11][12] The other superfamily, cis-defensins, contains the defensins found in invertebrates, plants, and fungi.[13][14][15] The superfamilies and families are determined by the overall tertiary structure, and each family usually has a conserved pattern of disulphide bonds.[9][16] All defensins form small and compact folded structures, typically with a high positive charge, that are highly stable due to the multiple disulphide bonds. In all families, the underlying genes responsible for defensin production are highly polymorphic.[citation needed]

Trans-defensins

[edit]

Vertebrate defensins are primarily α-defensins and β-defensins. Some primates additionally have the much smaller θ-defensins. In general, both α- and β-defensins are encoded by two-exon genes, where the first exon encodes for a hydrophobic leader sequence (removed after translation) and the cysteine-rich sequence (the mature peptide). The disulfide linkages formed by the cysteines have been suggested to be essential for activities related to innate immunity in mammals, but are not necessarily required for antimicrobial activity.[17][18] Theta defensins form a single beta-hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans.[19]

Table of human defensins
Type Gene Symbol Gene Name Protein Name Description
α-defensins DEFA1 Defensin, alpha 1 Neutrophil defensin 1 Are expressed primarily in neutrophils as well as in NK cells and certain T-lymphocyte subsets. DEFA5 and DEFA6 are expressed in Paneth cells of the small intestine, where they may regulate and maintain microbial balance in the intestinal lumen.
DEFA1B Defensin, alpha 1B Defensin, alpha 1
DEFA3 Defensin, alpha 3, neutrophil-specific Neutrophil defensin 3
DEFA4 Defensin, alpha 4, corticostatin Neutrophil defensin 4
DEFA5 Defensin, alpha 5, Paneth cell-specific Defensin-5
DEFA6 Defensin, alpha 6, Paneth cell-specific Defensin-6
β-defensins DEFB1 Defensin, beta 1 Beta-defensin 1 Are the most widely distributed, being secreted by leukocytes and epithelial cells of many kinds. For example, they can be found on the tongue, skin, cornea, salivary glands, kidneys, esophagus, and respiratory tract. It has been suggested (but also challenged) that some of the pathology of cystic fibrosis arises from the inhibition of β-defensin activity on the epithelial surfaces of the lungs and trachea due to higher salt content.
DEFB2 Defensin, beta 2 Beta-defensin 2
DEFB3 Defensin, beta 3 Beta-defensin 3
DEFB103A Defensin, beta 103B Beta-defensin 103
... ... ...
DEFB106A Defensin, beta 106A Beta-defensin 106A
DEFB106B Defensin, beta 106B Beta-defensin 106B
DEFB107B Defensin, beta 107A Beta-defensin 107
DEFB110 Defensin, beta 110 Beta-defensin 110
... ... ...
DEFB136 Defensin, beta 136 Beta-defensin 136
θ-defensins DEFT1P Defensin, theta 1 pseudogene not expressed in humans Are rare, and thus far have been found only in the leukocytes of the rhesus macaque[20] and the olive baboon, Papio anubis, the gene coding for it is corrupted in humans and other primates.[21][22]

Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 'big defensins' are found in molluscs, arthropods and lancelets.[7][8]

Cis-defensins

[edit]

Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects).[23] Other invertebrates known to produce defensins from this protein superfamily include molluscs, annelids and cnidaria.[24]

Plant defensins were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples.[25] They have been identified in all major groups of vascular plants, but not in ferns, mosses or algae.[25]

Fungal defensins were first identified in 2005.[26] Studied examples mainly have anti-bacterial activities and have been found in both main divisions of fungi (Ascomycota and Basidiomycota), as well as in the more basal groups of Zygomycota and Glomeromycota.[27]

Bacterial defensins have also been identified, but are by far the least studied. They include variants with only four cysteines, whereas defensins from eukaryote defensins almost all have six or eight.[28]

[edit]

In addition to the defensins involved in host defence, there are a number of related Defensin-Like Peptides (DLPs) that have evolved to have other activities.

Toxins

[edit]

There appear to have been multiple evolutionary recruitments of defensins to be toxin proteins used in the venoms of animals;[29] they act via a completely different mechanism to their antimicrobial relatives, from binding directly to ion channels to disrupting nerve signals. Examples include the crotamine toxin in snake venom,[30] many scorpion toxins,[31] some sea anemone toxins,[10] and one of the toxins in platypus venom.[29] Indeed, an insect defensin has been experimentally converted into a toxin by deletion of a small loop that otherwise sterically hindered interactions with the ion channels.[32]

Signalling

[edit]

In vertebrates, some α- and β-defensins are involved in signalling between the innate immune and adaptive immune systems.[33][34] In plants, a specialised family of DLPs is involved in signalling to detect if self-pollination has occurred and induce self-incompatibility to prevent inbreeding.[35]

Enzyme inhibitors

[edit]

Some antimicrobial defensins also have enzyme inhibitory activity, and some DLPs function primarily as enzyme inhibitors, acting as antifeedants (discouraging animals from eating them).[36][37][38]

Function

[edit]

In immature marsupials, because their immune system is underdeveloped at the time of birth, defensins play a major role in defense against pathogens. [citation needed] They are produced in the milk of the mother as well as by the young marsupial in question.

In human breast milk, defensins play a central role in neonate immunity.[39]

The human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin,[40] retrocyclin, was created by 'fixing' the pseudogene, and it was shown to be effective against HIV[41] and other viruses, including herpes simplex virus and influenza A. They act primarily by preventing these viruses from entering their target cells.

Also interesting is the effect of alpha-defensins on the exotoxin produced by anthrax (Bacillus anthracis). Chun Kim et al. showed how anthrax, which produces a metalloprotease lethal factor (LF) protein to target MAPKK, is vulnerable to human neutrophil protein-1 (HNP-1). This group showed HNP-1 to behave as a reversible noncompetitive inhibitor of LF.[42]

They have generally been considered to contribute to mucosal health; however, it is possible that these peptides can be considered biological factors that can be upregulated by bioactive compounds present in human breast milk. In this sense, the intestinal production of antimicrobial peptides as hBD2 and hBD4 by trefoil from milk might play an important role on neonate colonization, thereby enhancing the immune response of newborns against pathogens with which they may come in contact.[39][43]

Pathology

[edit]

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer.[44]

An imbalance of defensins in the skin may contribute to acne.[45]

A reduction of ileal defensins may predispose to Crohn's disease.[46][47]

In one small study, a significant increase in alpha defensin levels was detected in T cell lysates of schizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings. The authors suggested that alpha-defensin levels might prove a useful marker for schizophrenia risk.[48]

Defensins are found in the human skin during inflammatory conditions like psoriasis[49] and also during wound healing.

Applications

[edit]

Defensins

[edit]

At present, the widespread spread of antibiotic resistance requires the search and development of new antimicrobial drugs. From this point of view, defensins (as well as antimicrobial peptides in general) are of great interest. It was shown that defensins have pronounced antibacterial activity against a wide range of pathogens.[50] In addition, defensins can enhance the effectiveness of conventional antibiotics.[50]

Defensin-mimetics

[edit]

Defensin mimetics, also called host defense peptide (HDP) mimetics, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity.[51] Similar molecules, such as brilacidin, are being developed as antibiotics,[52] anti-inflammatories for oral mucositis,[53][54] and antifungals, especially for candidiasis.[55][56][57]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Defensin

View on Grokipedia
from Grokipedia
Defensins are a of small, cationic (typically 2–5 kDa in size) that form a key component of the across eukaryotes, characterized by a conserved featuring six residues forming three intramolecular bonds that stabilize a predominantly β-sheet fold. These peptides exhibit broad-spectrum activity by disrupting the membranes of , fungi, viruses, and through mechanisms such as pore formation and membrane permeabilization, while also modulating immune responses via of immune cells and induction of cytokines. In mammals, including humans, defensins are classified into three subfamilies—α-defensins, β-defensins, and θ-defensins—distinguished by their disulfide connectivity patterns, with α- and β-defensins being the primary types in humans and θ-defensins unique to certain as circular peptides. Human α-defensins, such as human neutrophil peptides (HNP1–4) and human defensins 5 and 6 (HD5, HD6), are predominantly expressed in s and Paneth cells of the intestinal crypts, where they contribute to phagolysosomal killing and regulation of the . β-defensins (hBD-1 to hBD-4 and beyond) are mainly produced by epithelial cells at mucosal surfaces, providing frontline defense against pathogens and promoting and resolution. Beyond direct antimicrobial effects, defensins influence adaptive immunity by acting as adjuvants, enhancing , and exhibiting antiviral properties, such as inhibiting HIV-1 entry or via interactions with viral envelopes or host receptors like ACE2. Their therapeutic potential is highlighted by low propensity for resistance development, positioning them as promising candidates for novel antibiotics and antivirals, though challenges like stability and specificity remain. Defensins are evolutionarily conserved, with homologs in (e.g., antifungal γ-thionins) and , underscoring their ancient role in host defense predating adaptive immunity. Dysregulation of defensin expression has been linked to inflammatory diseases, infections, and cancers, emphasizing their broader biological significance in maintaining at barrier sites.

Overview and Discovery

Historical Background

The discovery of defensins began in 1985 when researchers isolated six from rabbit peritoneal s, naming them "defensins" due to their microbicidal activity against and fungi. These peptides, characterized by their small size (around 3-4 kDa), cationic nature, and six conserved residues forming three bonds, were the first members of what would become a major family of host defense peptides. In the same year, the term was applied to homologous peptides identified in s, termed human neutrophil peptides (HNP-1 to HNP-3). These were later expanded to include HNP-4 by 1989 through further purification and sequencing efforts. Beta-defensins in humans were discovered in the mid-1990s, starting with hBD-1 in 1995 from epithelial cells and followed by hBD-2 in 1997, hBD-3 in 2001, and hBD-4 in 2003, revealing their inducible expression in response to . Early research on defensins extended to non-vertebrates in the 1990s, with defensins first isolated from seeds in 1992, exemplified by Rs-AFP2, which demonstrated potent activity and a conserved cysteine-stabilized . Fungal defensins emerged later, with the first characterized in 2005 from the mushroom Pseudoplectania nigrella (plectasin) and shortly thereafter from species, highlighting their broad evolutionary distribution. Key milestones included the first structural elucidation of a defensin via NMR in 1988 for NP-5, revealing a compact β-sheet core stabilized by disulfide bonds, which informed subsequent studies on their amphipathic properties. In the , the identification of theta-defensins in , such as rhesus theta-defensin-1 in 1999, introduced cyclic variants formed by head-to-tail ligation of two α-defensin precursors, expanding the family's structural diversity. Initially, defensins were sometimes conflated with other neutrophil-derived antimicrobial peptides like cathelicidins, which share microbicidal roles but differ in precursor structure and processing; this distinction was clarified by the early 2000s through comparative genomic and biochemical analyses.

Definition and General Characteristics

Defensins are a family of small cationic peptides, typically comprising 18–45 amino acids, that play a central role in innate immunity across diverse organisms. These peptides exhibit a molecular weight of 2–5 kDa and carry a net positive charge ranging from +2 to +9 at physiological pH, which facilitates their interaction with negatively charged microbial membranes. Structurally, defensins are characterized by their cysteine-rich composition, featuring six conserved cysteine residues that form three intramolecular disulfide bonds, stabilizing a compact β-sheet core with amphipathic properties—allowing both hydrophobic and hydrophilic regions to engage targets effectively. Evolutionarily conserved, defensins are present in vertebrates, invertebrates, plants, fungi, and even bacteria— with five classes of bacterial cis-defensins identified as of 2024, suggesting deep ancestral origins—underscoring their ancient role and broad adaptive significance in host defense. In these organisms, they contribute to protection against bacteria, fungi, viruses, and other pathogens by disrupting microbial membranes, modulating immune responses, and promoting resolution. This widespread distribution highlights defensins as a cornerstone of innate immune systems, with structural similarities suggesting despite independent lineages in some cases. In vertebrates, defensins are prominently distributed in neutrophils, where α-defensins reside in azurophilic granules; epithelial cells lining the skin, lungs, and mucosa; the gut, particularly in Paneth cells of the ; and the reproductive tract, including the and . Beyond animals, defensins are notably abundant in seeds, tubers, and floral tissues, aiding in defense against soil pathogens and supporting establishment. Such localization ensures rapid deployment at barrier sites vulnerable to .

Molecular Structure

Conserved Features

Defensins are characterized by a highly conserved γ-core motif, represented as Cys-(X)5-6-Cys-(X)2-4-Cys, which forms the structural backbone common to all family members and is stabilized by invariant bridges. This motif integrates two short antiparallel β-strands connected by a loop, conferring thermal, proteolytic, and chemical stability essential for their antimicrobial roles. The triad in the γ-core enables the formation of a compact, -linked scaffold that is preserved across diverse defensin classes, from vertebrates to and even analogs. The disulfide bonding patterns further underscore this conservation, with six cysteine residues typically forming three intramolecular bridges that lock the structure into a stable fold. In β-defensins, the pairing follows a cis configuration: C1-C5, C2-C4, and C3-C6, creating a triple-stranded antiparallel β-sheet core. In contrast, α-defensins exhibit a trans configuration with C1-C6, C2-C4, and C3-C5 pairings, often incorporating an N-terminal α-helical segment alongside a triple-stranded β-sheet. These patterns, determined through extensive sequence alignments and structural studies, ensure a rigid, globular architecture approximately 30-45 in length, resistant to unfolding under physiological stresses. High-resolution structural insights from and NMR spectroscopy reveal the compact, dimeric β-sheet architecture in many defensins, exemplified by the human neutrophil peptide HNP-3 (PDB: 1DFN). At 1.9 Å resolution, the HNP-3 structure displays a tightly packed with hydrophobic interfaces mediating dimerization, while the exposed cationic face facilitates interactions with anionic targets. Similar analyses across defensins confirm the γ-core's role in maintaining this conserved , with bonds reducing conformational to enhance functional specificity. A hallmark of defensin conservation is their amphipathic nature, featuring segregated hydrophobic and hydrophilic regions that enable insertion and disruption. This property arises from a net positive charge, typically ranging from +2 to +9, calculated as the sum of basic residues (, , ) minus acidic ones (, ), which promotes electrostatic attraction to negatively charged microbial membranes. Such features, uniform across defensin superfamilies, underpin their broad-spectrum activity without compromising host cell selectivity.

Structural Variations

Alpha-defensins feature a characteristic triple-stranded antiparallel β-sheet core paired with an N-terminal α-helix, stabilized by three intramolecular bonds including a distinctive cis-paired bond between C2 and C4. This configuration arises from the specific cysteine pairing pattern (C1-C6, C2-C4, C3-C5), which differs from other defensin types while maintaining the conserved six- motif. Beta-defensins share a similar triple-stranded β-sheet structure but exhibit greater variability in inter-cysteine loop lengths and, in certain isoforms, extended C-terminal regions that contribute to structural diversity across species. For instance, β-defensin 3 (HBD3) displays a short C-terminal extension beyond the core β-sheet, contrasting with the more compact termini in HBD1. These variations in loop flexibility and extensions allow for adaptations in monomer-dimer equilibria and surface properties without altering the fundamental connectivity. Theta-defensins represent a unique circular , formed through head-to-tail ligation of two nonapeptides to yield an 18-residue containing three antiparallel β-strands and a ladder of three bonds. This cyclic backbone, exclusive to monkeys such as rhesus macaques, lacks free N- and C-termini, enhancing rigidity and stability compared to linear defensins. Plant and fungal cis-defensins are notably larger, typically comprising 46–54 with eight cysteines forming four bonds in a cis configuration, often incorporating an additional α- alongside the core CSαβ motif of one and a small β-sheet. Some variants adopt a knottin-like fold, characterized by a compact β-sheet intertwined by bonds, as seen in certain seed-expressed peptides. These structural elements build on the conserved patterns by extending the scaffold for species-specific adaptations. Recent discoveries from 2023–2025 highlight marine invertebrate defensins, such as β-defensin-like peptides from sea anemones like Heteractis magnifica, which exhibit toxin-like neurotoxic properties through modulation. These variants, identified via venomics, underscore evolutionary convergence in structural plasticity. In 2025, structures of bacterial cis-defensins were elucidated, demonstrating trans-kingdom conservation of the defensin fold with eukaryotic homologs.

Classification and Varieties

Vertebrate Defensins

defensins are a subclass of primarily found in mammals, birds, and other , distinguished by their cysteine-rich structures and roles in innate immunity. They are categorized into three main subfamilies—, and —based on their disulfide bonding patterns and sequences. -defensins feature three disulfide bonds in a 1-6, 2-4, 3-5 configuration, while beta-defensins have a 1-5, 2-4, 3-6 pattern, but with greater sequence diversity; -defensins are unique in their cyclic structure formed by ligation. These peptides are expressed in various epithelial and immune cells, contributing to barrier defense against pathogens. In humans, alpha-defensins consist of six members: human neutrophil peptides 1–4 (HNP1–4), which are abundantly expressed in s and comprise 30–50% of the protein content in their azurophilic granules, and human defensins 5 and 6 (HD5 and HD6), produced primarily by Paneth cells in the . HNP1–4 are stored in azurophilic granules and released during to target , fungi, and viruses, while HD5 and HD6 maintain gut by shaping the intestinal and exhibiting lectin-like activity against pathogens such as . These peptides demonstrate broad-spectrum antimicrobial effects, with HD5 disrupting bacterial membranes and HD6 forming nanonets to entrap microbes. Beta-defensins are the most diverse in vertebrates, with over 30 genes identified in the , though hBD-1 through hBD-4 are the best-characterized. hBD-1 is constitutively expressed in epithelial tissues such as , lungs, and urinary tract, providing baseline protection, whereas hBD-2, hBD-3, and hBD-4 are inducible by microbial stimuli or cytokines like IL-1 and TNF-α in mucosal and epithelia. For instance, hBD-2 is upregulated in during infection, targeting , while hBD-3 exhibits potent activity against both Gram-positive and -negative bacteria, fungi, and enveloped viruses. These peptides are crucial for and mucosal , with expression patterns varying by tissue to adapt to local microbial challenges. Theta-defensins are cyclic peptides exclusive to certain primates, such as rhesus macaques, where three isoforms—rhesus theta-defensins 1–3 (RTD-1 to RTD-3)—are produced from two precursor genes via enzymatic ligation of nonapeptides. RTD-1, the prototype, is expressed in leukocytes and , exhibiting antimicrobial activity against , fungi, and HIV-1 by disrupting microbial membranes and inhibiting viral entry. In humans, theta-defensin genes exist as inactive pseudogenes known as retrocyclins, which encode linear peptides lacking the cyclization machinery, rendering them non-functional. This evolutionary loss in hominids highlights species-specific adaptations in innate immunity. The genes encoding defensins are organized in clusters: alpha-defensins (DEFA1–6) form a tandem array on 8p23.1, while beta-defensin genes (DEFB) are distributed across clusters on 8p23.1 (including DEFB4, DEFB103–107) and 20q11.2 (including DEFB109–118). These clusters exhibit significant copy number variations (CNVs), particularly in the beta-defensin locus on 8p23.1, where healthy individuals range from 2 to 12 copies, influencing defensin expression levels and susceptibility to infections like and . Low copy numbers of DEFB4 correlate with reduced hBD-2 production and altered mucosal . Recent genomic studies as of 2025 have identified novel beta-defensin isoforms, such as variants of hBD-2 and hBD-3, linked to modulation of the skin in conditions like and . For example, CNVs and single-nucleotide polymorphisms in DEFB genes influence microbial composition on the skin, promoting beneficial commensals while suppressing pathogens, as evidenced in analyses of diverse populations. These findings underscore the role of in host-microbe interactions.

Non-Vertebrate Defensins

Non-vertebrate defensins encompass a diverse group of found across , , fungi, and , characterized by cysteine-stabilized structures that confer stability and broad-spectrum activity against pathogens. In , these peptides often adopt a cis-defensin fold, distinct from the theta-defensin configuration in some vertebrates, and play crucial roles in innate immunity. In insects such as , cis-defensins like drosomycin exemplify this class; this 44-residue peptide is inducibly expressed in response to and exhibits potent activity by disrupting microbial membranes. Drosomycin's structure features a conserved array forming three disulfide bonds, enabling its interaction with fungal targets, and it represents a key component of the insect immune response triggered by the Toll pathway. Marine invertebrates, particularly bivalves like mussels (Mytilus galloprovincialis), produce big defensins, which are larger variants (around 80-100 residues) with an N-terminal hydrophobic domain linked to a classical defensin C-terminal domain via a linker. These big defensins, such as those identified in mussel hemocytes, display activity against Gram-positive and , with evolutionary diversification driven by gene presence/absence variation that enhances host adaptability to marine pathogens. Plant defensins, numbering approximately 300 identified sequences across various , are small (45-54 residues) cationic peptides with a characteristic cysteine-stabilized αβ (CSαβ) motif, often expressed in a tissue-specific manner. Seed-specific defensins, including gamma-thionins from and , accumulate in to protect against fungal and bacterial invasion during germination, while floral defensins target pollinator-associated microbes. A prominent example is RsAFP2 from ( sativus), which exhibits strong activity by binding glucosylceramides in fungal membranes, inducing stress and apoptosis-like responses in pathogens like . Evolutionary analyses indicate that defensins arose from ancient duplications, with diversification into subfamilies reflecting adaptations to specific ecological niches, as evidenced by genomic studies in model like . Fungal defensins, first discovered in 2005 with plectasin from the saprophytic mushroom Pseudoplectania nigrella, are typically acidic peptides (40-50 residues) that adopt a CSαβ fold and contribute to hyphal defense against bacterial competitors. Plectasin potently inhibits , including methicillin-resistant Staphylococcus aureus, by targeting lipid II in synthesis, a mechanism distinct from many eukaryotic defensins. Recent surveys reveal greater fungal diversity, with over 100 homologs identified across and , including variants like eurocin from Eurotium amstelodami that protect against soil microbes; these peptides often cluster in genomes near biosynthetic genes, suggesting coordinated defense strategies. Bacterial defensins are rare and atypical, lacking the full complement of cysteines found in eukaryotic forms; examples include short linear peptides in Pseudomonas species, such as those derived from β-defensin-like sequences, which exhibit antimicrobial activity through membrane disruption without stabilized folds. In Pseudomonas aeruginosa, these linear variants contribute to biofilm defense and quorum sensing modulation, representing an evolutionary convergence on defensin-like functions in prokaryotes.

Biosynthesis and Regulation

Genetic Organization

Defensin genes are typically organized into multi-gene families, often arranged in tandem arrays within the to facilitate coordinated expression and evolutionary adaptability. In humans, the alpha-defensin genes, such as DEFA1 and DEFA3, form a copy-variable cluster on 8p23.1, with copy numbers ranging from 4 to 11 per diploid due to recurrent duplications and deletions. This structural variation contributes to inter-individual differences in defensin production levels. Similarly, the beta-defensin on the same chromosomal region includes multiple paralogs like DEFB4 and DEFB103, exhibiting 2 to 8 copies per diploid , reflecting ongoing genomic instability in these loci. Promoter regions of defensin genes contain regulatory elements that support inducible expression in response to environmental cues. For instance, the promoter of the human beta-defensin 2 gene (DEFB4 or hBD-2) includes multiple binding sites, such as the proximal κB1 site at position -188, which mediate transcriptional activation during . Additionally, STAT and NF-IL6 sites in the hBD-2 promoter cooperate with to fine-tune expression, ensuring rapid upregulation upon microbial challenge without constitutive activity. These motifs are conserved across many defensin promoters, highlighting their role in linking genomic organization to functional responsiveness. The evolutionary history of defensin genes is marked by gene duplication events that expanded family diversity across kingdoms. In vertebrates, successive duplications within clusters, such as the primate beta-defensin locus on chromosome 8p22-23, have generated paralogous genes through birth-and-death processes, allowing adaptation to pathogen pressures over millions of years. Animal defensin precursors date back at least 500 million years to early bilaterian ancestors. Plant defensins, part of the cis-defensin superfamily that encompasses knottin-like peptides, trace their origins to an ancient inhibitor cystine knot (ICK) motif that evolved independently from animal defensins. This convergent evolution underscores the independent emergence of defensin-like structures in plants and animals from distinct progenitors. Genetic polymorphisms further shape defensin gene function and disease risk. Single nucleotide polymorphisms (SNPs) in DEFB1, such as rs11362 (G>A), are associated with altered beta-defensin 1 expression and increased susceptibility to conditions like and periodontitis by impairing innate mucosal defense. Copy number variations in alpha-defensin genes, including expansions or contractions in the DEFA1/DEFA3 array, correlate with varying levels of antimicrobial peptide output and influence outcomes in infections such as urinary tract infections.

Expression and Cellular Sources

Defensins are primarily synthesized as precursor proteins that undergo post-translational processing to generate mature, active forms. In mammals, alpha-defensins such as human peptides (HNPs) are produced as prepropeptides in promyelocytes, where the is cleaved to yield inactive proHNPs, which are then further processed in azurophilic granules by and proteinase 3 to remove the pro-region and form the mature 29-30 residue peptides stored in these granules. Beta-defensins follow a similar pathway, with propeptides cleaved by furin-like proprotein convertases in the Golgi apparatus before packaging into secretory granules or lamellar bodies for release. These mature defensins are stored in a concentrated, inactive form within granules until triggered for , ensuring rapid deployment during immune responses. Transcriptional regulation of defensin genes is tightly controlled to respond to environmental cues, with expression upregulated by microbial components recognized via Toll-like receptors (TLRs) and proinflammatory cytokines such as IL-1 and TNF-alpha. For instance, bacterial activates TLR4, leading to translocation and enhanced transcription of beta-defensin genes in epithelial cells. Cytokines like TNF-alpha further amplify this by binding to their receptors, activating MAPK and pathways that drive defensin promoter activity. In , analogous regulation occurs through pattern recognition receptors that sense microbial patterns, inducing defensin expression via signaling. Cellular sources of defensins vary by type and organism, reflecting their roles in innate immunity at barrier sites. In vertebrates, alpha-defensins are predominantly expressed in neutrophils, where HNPs constitute up to 50% of azurophilic granule protein content, and in Paneth cells of the , which secrete human defensins 5 and 6 (HD5/6) into the gut lumen to maintain microbial . Beta-defensins are mainly produced by epithelial cells lining mucosal surfaces, , and airways, providing a first line of defense against pathogens at these interfaces. In plants, defensins are expressed in vascular tissues, seeds, and roots, with accumulation in and to protect against vascular pathogens. Developmentally, defensin expression supports early immunity; in humans, beta-defensins such as hBD-2 are transferred via to neonates, bolstering their immature against gastrointestinal infections. Additionally, induces hBD-2 expression in through binding to response elements in the hBD-2 promoter, enhancing defenses during environmental exposure. Recent studies as of highlight how plant root microbiomes influence defensin expression through signaling pathways; for example, beneficial root-associated microbes activate jasmonate-dependent transcription of plant defensin 1.2 (PDF1.2), modulating immune responses to pathogens via root exudates and microbial elicitors.

Biological Functions

Antimicrobial Activity

Defensins exert their effects primarily through direct interactions with microbial targets, leveraging their cationic and amphipathic properties to disrupt cellular integrity. These peptides, typically 2-5 kDa in size, are attracted to the negatively charged surfaces of microbial membranes via electrostatic interactions between their positive charges and the anionic phospholipids or lipopolysaccharides present on and fungi. This initial binding facilitates subsequent mechanisms of action, with minimal inhibitory concentrations (MICs) often ranging from 1 to 10 μM against susceptible pathogens. A key mechanism involves membrane disruption, where defensins insert into lipid bilayers to form pores or cause leakage. Proposed models include the barrel-stave pore, in which peptides align to create a transmembrane channel (as seen with human α-defensin HD5 against Gram-negative bacteria); the toroidal pore, where peptides induce membrane curvature; and the carpet model, leading to detergent-like solubilization of the membrane. For instance, human neutrophil peptide-1 (HNP-1) permeabilizes the outer and inner membranes of Escherichia coli, leading to rapid depolarization and cell death. Beyond membranes, defensins target intracellular processes, such as binding to lipid II to inhibit cell wall synthesis in Gram-positive bacteria or suppressing DNA, RNA, and protein synthesis in E. coli by HNP-1. Human β-defensin 3 (hBD-3) demonstrates MICs of approximately 1 mg/L against Staphylococcus aureus and 4 mg/L against E. coli, highlighting potency across Gram-positive and Gram-negative bacteria. Defensins exhibit a broad spectrum of activity, including against fungi like and enveloped viruses such as HIV-1. Against fungi, vertebrate defensins disrupt ergosterol-enriched membranes, while plant defensins often bind in the cell wall to inhibit growth. Fungal defensin-like peptides, for example, the antifungal protein AFP from Aspergillus giganteus, target chitin synthases, arresting hyphal development in pathogens like species. For viruses, α-defensins such as HNP-1 and HD5 block HIV-1 entry by binding to gp120 or , preventing fusion with host cells and reducing infectivity. Synergistic effects enhance efficacy, as defensins like hBD-3 or LL-37 (a related ) potentiate antibiotics such as and against resistant bacteria, lowering required doses and combating multidrug resistance. In plants, defensins like RsAFP2 from inhibit growth via glucosylceramide binding, complementing chitin interactions for fungal control.

Immunomodulatory Roles

Defensins exert significant chemotactic effects on immune cells, orchestrating the recruitment of key players in the innate and adaptive immune responses. Human β-defensin 2 (hBD-2) acts as a potent chemoattractant for tumor factor-α (TNF-α)-stimulated neutrophils, immature dendritic cells, and memory T cells by binding to the CCR6, thereby bridging antimicrobial defense with adaptive immunity. Similarly, human β-defensin 3 (hBD-3) recruits monocytes and dendritic cells through CCR6 interaction, enhancing immune cell migration to sites of or . These activities underscore defensins' role in amplifying localized immune surveillance without direct engagement. Beyond , defensins modulate profiles to fine-tune inflammatory responses in macrophages and other immune cells. Human peptides (HNPs), a type of α-defensin, upregulate interleukin-8 (IL-8) production in macrophages via and IRF1 pathways, promoting further recruitment. HNPs also enhance TNF-α secretion from peripheral blood mononuclear cells and monocyte-derived macrophages, amplifying pro-inflammatory signaling. Conversely, hBD-3 inhibits IL-10 production in lipopolysaccharide-stimulated macrophages, shifting the balance toward sustained inflammation while suppressing anti-inflammatory feedback. In , defensins support tissue repair by promoting and epithelial regeneration. hBD-3 accelerates cutaneous wound closure in murine models, with treated wounds showing complete healing by day 12 compared to day 16 in controls, through increased accumulation and vascularization. It induces the expression of angiogenic growth factors such as (VEGF) and (FGF) in fibroblasts and wound tissues, fostering new vessel formation as early as day 6 post-injury. Furthermore, hBD-3 stimulates migration and proliferation via the FGFR/JAK2/ signaling pathway, essential for re-epithelialization. Defensins contribute to immune tolerance by influencing regulatory T-cell (Treg) differentiation and function, particularly at low exposure levels. Mouse β-defensin 14 (mBD14) promotes IL-4 secretion and Treg responses through Toll-like receptor 2 (TLR2) activation on B cells, thereby preventing autoimmune diabetes in experimental models. A 2023 review further elucidates β-defensins' involvement in reproductive immunity, where human β-defensin 1 (hBD-1) enhances and triggers the via CCR6-mediated cAMP/PKA signaling and Ca²⁺ influx, with deficiencies linked to and impaired fertilization.

Role in Pathology

Disease Associations with Deficiency

Deficiencies in defensin production have been implicated in several human diseases, primarily through impaired antimicrobial barriers and increased susceptibility to infections. In Crohn's disease, a chronic inflammatory bowel disorder, reduced expression of human α-defensins HD5 and HD6 in the ileum is observed due to dysfunction of Paneth cells, which are specialized epithelial cells responsible for secreting these peptides into the intestinal lumen. This deficiency is particularly pronounced in patients with NOD2 (also known as CARD15) mutations, a genetic variant associated with up to 30-40% of ileal Crohn's cases, as NOD2 normally regulates Paneth cell function and defensin expression. The resulting diminished antimicrobial activity contributes to microbial dysbiosis and persistent inflammation in the gut mucosa. In skin disorders, low levels of human β-defensin 2 (hBD-2) are linked to heightened infection risk in , where impaired induction of this peptide in fails to control bacterial colonization, such as by . This contrasts with , where hBD-2 expression is markedly elevated, highlighting an inverse relationship that underscores defensin deficiency as a vulnerability factor in barrier-disrupted conditions like . Recent analyses confirm that hBD-2 mRNA and protein levels remain significantly lower in lesions compared to psoriatic ones, correlating with disease severity and infection propensity. Neonatal sepsis risk is elevated in preterm infants exposed to breast milk with low defensin concentrations, as these peptides provide critical protection against common pathogens like Group B . Preterm milk and often exhibit reduced β-defensin levels, contributing to immature immune defenses and higher rates. Similarly, susceptibility to HIV-1 stems from the evolutionary loss of functional retrocyclins, θ-defensins that inhibit viral entry by targeting the gp120 envelope protein; a mutation renders these peptides non-functional in modern s, unlike in rhesus macaques where they confer protection. This deficiency may partially explain heightened HIV transmission risks in populations. In non-vertebrate models, plant defensin deficiencies illustrate conserved roles in fungal defense; knockout mutants of genes encoding PDF1.2a and PDF1.2b show reduced expression of these and increased susceptibility to necrotrophic fungi like Alternaria brassicicola and , due to impaired jasmonate-mediated responses. Double mutants exhibit exacerbated disease symptoms, confirming the peptides' contribution to basal resistance against root and foliar pathogens. Emerging 2025 research highlights β-defensin genetic variants as drivers of , with polymorphisms altering function leading to imbalanced gut communities and heightened inflammation in conditions like . Studies also link β-defensin-1 induction via AhR pathways to restored in models, suggesting deficiency exacerbates . These findings underscore ongoing investigations into defensin variants as modifiable factors in microbial-immune interactions.

Disease Associations with Dysregulation

Dysregulation of defensin expression, particularly overexpression or aberrant activity, has been implicated in several pathological conditions where elevated levels contribute to progression rather than resolution. In , human neutrophil peptides (HNPs), also known as alpha-defensins 1-3, are markedly elevated in colorectal tumors and associated with advanced stages. Studies have shown that plasma and tumor tissue levels of HNP1-3 are significantly higher in patients with exhibiting lymphatic or hepatic compared to those with localized , suggesting a role in promoting tumor invasion and spread. This elevation may enhance metastatic potential through interactions with host receptors, potentially amplifying pro-tumorigenic signaling in the . In autoimmune disorders, elevated alpha-defensins contribute to chronic inflammation by sustaining immune activation in affected tissues. For instance, in , alpha-defensin levels in are substantially higher than in patients, correlating with infiltration and joint destruction. This overexpression is thought to exacerbate synovial inflammation by recruiting additional immune cells and amplifying responses, thereby perpetuating the autoimmune response. Overexpression of human beta-defensin 2 (hBD-2) plays a detrimental role in inflammatory skin conditions such as vulgaris. In lesions, hBD-2 is upregulated in sebaceous glands and surrounding epithelium, particularly in pustular areas, where it intensifies local inflammation. This aberrant expression, triggered by microbial stimuli and cytokines, promotes excessive immune cell recruitment and tissue damage, worsening severity beyond defense. In chronic wounds, imbalanced beta-defensin expression hinders healing processes and may facilitate persistent infections. Human beta-defensin 2 (hBD-2) shows constitutively high baseline levels in tissues, unlike the inducible expression seen in acute injuries, which disrupts normal re-epithelialization and remodeling. This dysregulation delays wound closure by fostering a pro-inflammatory state that impairs tissue regeneration. Additionally, altered beta-defensin profiles have been linked to viral persistence, such as in human papillomavirus (HPV) infections, where insufficient or dysregulated antiviral activity allows chronicity and potential oncogenic progression. Recent 2024 research highlights the potential of theta-defensin analogs in addressing primate-specific inflammatory disorders. These synthetic macrocyclic peptides, derived from circular theta-defensins found in monkeys, demonstrate effects by inhibiting IL-6 production and TNF signaling pathways. Such analogs offer promise for modulating excessive in conditions like autoimmune or chronic inflammatory diseases unique to .

Therapeutic Applications

Natural Defensins in Medicine

Recombinant human β-defensin-3 (hBD-3) has shown promise in topical applications for promoting , particularly in infected or diabetic wounds, by enhancing migration, proliferation, and through pathways such as FGFR/JAK2/ signaling. In preclinical models, topical administration of recombinant hBD-3 accelerated closure of Staphylococcus aureus-infected diabetic wounds in mice, reducing bacterial load and inflammation while stimulating tissue regeneration. Although clinical trials for recombinant hBD-3 in remain in early stages as of 2025, its dual and pro-healing properties position it as a for advanced therapeutic development. For oral delivery, recombinant forms of human α-defensins HD5 and HD6, produced by Paneth cells in the gut, have been explored for treating intestinal infections due to their role in shaping and entrapping pathogens like . These defensins form nanonets to prevent bacterial translocation across the mucosal barrier, offering potential in combating gut and infections such as those caused by enteropathogens. In plant-based applications, the alfalfa defensin alfAFP, when expressed transgenically in plants, confers robust resistance against fungal pathogens like Verticillium dahliae in both and field conditions, demonstrating the utility of natural defensins in crop protection without compromising yield. Defensins also serve as vaccine adjuvants to bolster immune responses, particularly in , by recruiting immune cells and enhancing . For instance, murine β-defensin-2 (Mbd2) co-administration with an adenovirus-based in animal models increased neutralizing titers and improved protection against viral challenge, highlighting its potential to induce rapid humoral and cellular immunity. Despite these advances, challenges in using natural defensins therapeutically include their limited stability in physiological environments, potential to host cells at high concentrations, and difficulties in scalable production. In models, however, recombinant defensins like bovine β-defensins have demonstrated success by reducing bacterial dissemination and inflammation without observed toxicity in intestinal epithelial cells or animal hosts. Marine-derived defensins from invertebrates show promise in preclinical evaluations for antifungal applications, demonstrating broad-spectrum activity against drug-resistant fungi like Candida auris and low mammalian toxicity.

Synthetic Defensin Mimetics

Synthetic defensin mimetics are engineered compounds designed to replicate the antimicrobial and immunomodulatory properties of natural defensins while overcoming limitations such as poor stability, high production costs, and associated with native peptides. These mimetics typically incorporate key structural motifs from defensins, such as cationic amphipathic regions, to disrupt microbial membranes or modulate host immune responses, and are developed through or computational optimization for therapeutic applications. Peptidomimetics represent a major class of synthetic analogs, often featuring cyclic structures to enhance proteolytic resistance and bioavailability. A prominent example is NZ2114, a variant of the fungal defensin-like plectasin, engineered through to improve activity against . NZ2114 demonstrates superior efficacy compared to in reducing methicillin-resistant Staphylococcus aureus (MRSA) loads in experimental models, achieving significant bacterial clearance in target tissues after three days of treatment at 20 mg/kg dosing. This cyclic targets lipid II in bacterial cell walls, similar to natural defensins, but with optimized for intravenous administration. Non-peptide mimetics, such as brilacidin, further diverge from natural defensin scaffolds by using small-molecule or designs to mimic membrane-disrupting functions without relying on full sequences. Brilacidin, a cationic steroid-based compound, has completed Phase 2b clinical trials for acute bacterial skin and skin structure infections (ABSSSI), showing comparable efficacy to in treating MRSA and other Gram-positive pathogens while exhibiting a favorable safety profile with low rates of . Its mechanism involves binding to bacterial membranes via motifs akin to polymyxin B (PMB), promoting pore formation and cell lysis. Design strategies for these mimetics emphasize incorporating the conserved γ-core motif—a short, disulfide-stabilized loop central to defensin activity—to confer stability against degradation and broad-spectrum potency. This motif, derived from the amphipathic core of and defensins, enables targeted insertion and has been used to create truncated peptides with retained and antibacterial effects, such as those inhibiting fungal proton pumps or bacterial growth at micromolar concentrations. Recent advances include AI-optimized designs, where models generate sequences with enhanced broad-spectrum activity against multidrug-resistant pathogens. These computational approaches prioritize motifs for PMB-like binding to improve selectivity and reduce off-target effects. Advantages of synthetic mimetics over natural defensins include improved oral through non-peptide scaffolds and reduced via sequence modifications that minimize host recognition as foreign antigens. For instance, γ-core-based designs exhibit greater serum stability and lower hemolytic activity compared to full-length peptides, enabling safer systemic use. In the therapeutic pipeline, defensin-inspired mimetics are advancing as antivirals, with brilacidin demonstrating inhibition of replication in vitro by targeting viral entry and envelope proteins, effective against variants including Delta and at low micromolar doses. Additionally, plant-derived γ-core mimetics, such as those from defensin MtDef4, are being developed for agricultural applications to combat fungal pathogens like , offering eco-friendly alternatives to chemical fungicides with multifaceted modes of action including permeabilization and inhibition.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC7149371/
  2. https://pubmed.ncbi.nlm.nih.gov/39693007/
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC7224315/
  4. https://pubmed.ncbi.nlm.nih.gov/3885968/
  5. https://pubmed.ncbi.nlm.nih.gov/2997278/
  6. https://pubmed.ncbi.nlm.nih.gov/2715246/
  7. https://pubmed.ncbi.nlm.nih.gov/8589110/
  8. https://pubmed.ncbi.nlm.nih.gov/9250591/
  9. https://pubmed.ncbi.nlm.nih.gov/11435451/
  10. https://pubmed.ncbi.nlm.nih.gov/12692021/
  11. https://pubmed.ncbi.nlm.nih.gov/1565652/
  12. https://pubmed.ncbi.nlm.nih.gov/16223961/
  13. https://pubmed.ncbi.nlm.nih.gov/2843652/
  14. https://pubmed.ncbi.nlm.nih.gov/10531000/
  15. https://www.nature.com/articles/s41392-023-01553-x
  16. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/defensin-beta-1
  17. https://pubs.acs.org/doi/10.1021/acsomega.4c06956
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC6784047/
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC11561630/
  20. https://pmc.ncbi.nlm.nih.gov/articles/PMC2819505/
  21. https://www.pnas.org/doi/10.1073/pnas.0401567101
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC7432377/
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC10015202/
  24. https://www.sciencedirect.com/science/article/pii/S0005273612004026
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC10662769/
  26. https://www.sciencedirect.com/science/article/pii/S0021925820478949
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC7159640/
  28. https://www.sciencedirect.com/topics/medicine-and-dentistry/knottin
  29. https://www.mdpi.com/1660-3397/22/2/71
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC12284004/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC4451809/
  32. https://www.science.org/doi/10.1126/science.1218831
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC2242434/
  34. https://pubmed.ncbi.nlm.nih.gov/3040155/
  35. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2012.00294/full
  36. https://pubmed.ncbi.nlm.nih.gov/26874342/
  37. https://journals.asm.org/doi/10.1128/iai.01100-08
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC4511374/
  39. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000095
  40. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2015.00115/full
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC1559531/
  42. https://pubmed.ncbi.nlm.nih.gov/24867293/
  43. https://www.jci.org/articles/view/184315
  44. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06723-9
  45. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2014.00097/full
  46. https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2017.00045/full
  47. https://resjournals.onlinelibrary.wiley.com/doi/10.1111/j.1365-2583.2009.00907.x
  48. https://www.annualreviews.org/content/journals/10.1146/annurev-micro-101923-100221
  49. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00758/full
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC7203481/
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC6473878/
  52. https://www.sciencedirect.com/science/article/pii/S019697810900045X
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC2592890/
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC8877149/
  55. https://link.springer.com/article/10.1007/s00253-024-13118-1
  56. https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-018-1190-z
  57. https://academic.oup.com/hmg/article/14/14/2045/608373
  58. https://www.sciencedirect.com/science/article/pii/S0888754305001576
  59. https://pubmed.ncbi.nlm.nih.gov/11781391/
  60. https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.71.1.154
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC156587/
  62. https://www.sciencedirect.com/science/article/abs/pii/S108495211730469X
  63. https://www.researchgate.net/publication/285223484_Antimicrobial_Peptides_Their_History_Evolution_and_Functional_Promiscuity
  64. https://www.tandfonline.com/doi/abs/10.1080/00365520701682615
  65. https://pubmed.ncbi.nlm.nih.gov/28485077/
  66. https://pubmed.ncbi.nlm.nih.gov/22448222/
  67. https://onlinelibrary.wiley.com/doi/10.1002/9780470514658.ch4
  68. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00448/full
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC97109/
  70. https://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2005.00590.x
  71. https://www.sciencedirect.com/topics/neuroscience/defensin
  72. https://www.tandfonline.com/doi/pdf/10.4161/gmcr.1.5.15091
  73. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00584/full
  74. https://onlinelibrary.wiley.com/doi/10.1111/cei.13013
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC12371161/
  76. https://pubmed.ncbi.nlm.nih.gov/12949495/
  77. https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-021-00343-2
  78. https://www.sciencedirect.com/science/article/pii/S0014579310001985
  79. https://pmc.ncbi.nlm.nih.gov/articles/PMC3842434/
  80. https://pmc.ncbi.nlm.nih.gov/articles/PMC4187972/
  81. https://pmc.ncbi.nlm.nih.gov/articles/PMC133099/
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC6485945/
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC8476922/
  84. https://pmc.ncbi.nlm.nih.gov/articles/PMC10334010/
  85. https://www.pnas.org/doi/10.1073/pnas.0505256102
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC1774270/
  87. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00646/full
  88. https://www.nejm.org/doi/full/10.1056/NEJMoa021481
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC5629447/
  90. https://www.jidonline.org/article/S0022-202X%2815%2932574-4/fulltext
  91. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117038
  92. https://pmc.ncbi.nlm.nih.gov/articles/PMC7158364/
  93. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035995
  94. https://apsjournals.apsnet.org/doi/pdf/10.1094/MPMI-20-11-1384
  95. https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202416324
  96. https://www.sciencedirect.com/science/article/abs/pii/S0378111925002574
  97. https://pubmed.ncbi.nlm.nih.gov/17015013/
  98. https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-5-8
  99. https://erar.springeropen.com/articles/10.1186/s43166-020-00026-1
  100. https://pubmed.ncbi.nlm.nih.gov/14568392/
  101. https://www.sciencedirect.com/science/article/pii/S0022202X15414307
  102. https://pubmed.ncbi.nlm.nih.gov/15260809/
  103. https://pmc.ncbi.nlm.nih.gov/articles/PMC1360544/
  104. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1406886/pdf
  105. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.712781/full
  106. https://www.researchgate.net/publication/23712543_Human_beta-defensin-3_promotes_wound_healing_in_infected_diabetic_wounds
  107. https://journals.physiology.org/doi/full/10.1152/ajpcell.00080.2022
  108. https://pubs.acs.org/doi/10.1021/ja5057906
  109. https://pubmed.ncbi.nlm.nih.gov/11101813/
  110. https://www.sciencedirect.com/science/article/abs/pii/S0168170217306500
  111. https://www.sciencedirect.com/science/article/abs/pii/S0168170213003055
  112. https://www.sciencedirect.com/science/article/abs/pii/S0169409X21004014
  113. https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-025-01601-0
  114. https://pmc.ncbi.nlm.nih.gov/articles/PMC12383081/
  115. https://pmc.ncbi.nlm.nih.gov/articles/PMC8686049/
  116. https://pmc.ncbi.nlm.nih.gov/articles/PMC3195053/
  117. https://www.researchgate.net/publication/51588689_Efficacy_of_NZ2114_a_Novel_Plectasin-Derived_Cationic_Antimicrobial_Peptide_Antibiotic_in_Experimental_Endocarditis_Due_to_Methicillin-Resistant_Staphylococcus_aureus
  118. https://www.clinicaltrials.gov/study/NCT02052388
  119. https://pmc.ncbi.nlm.nih.gov/articles/PMC12140270/
  120. https://pmc.ncbi.nlm.nih.gov/articles/PMC9820530/
  121. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.632008/full
  122. https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00094
  123. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202002330RR
  124. https://journals.asm.org/doi/abs/10.1128/aac.01700-24
  125. https://pmc.ncbi.nlm.nih.gov/articles/PMC10346373/
Add your contribution
Related Hubs
User Avatar
No comments yet.