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Alphabody
Alphabodies, also known as Cell-Penetrating Alphabodies or CPAB for short, are small 10 kDa proteins engineered to bind to a variety of antigens. Despite their name, they are not structurally similar to antibodies, which makes them a type of antibody mimetic. Alphabodies are different from many other antibody mimetics in their ability to reach and bind to intracellular protein targets. Their single chain alpha-helical structure is designed by computer modelling, inspired by naturally existing coiled-coil protein structures. Alphabodies are being developed by the Belgian biotechnology company Complix N.V. as potential new pharmaceutical drugs against cancer and autoimmune disease. In 2012, a collaboration agreement was signed with Monsanto to develop the technology for agricultural applications as well.
Alphabodies are developed as scaffolds with a set of amino acid residues that can be modified to bind protein targets, while maintaining correct folding and thermostability.
The Alphabody scaffold is computationally designed based on coiled-coil structures, but it has no known counterpart in nature. Initially, the scaffold was made of three peptides that associated non-covalently to form a parallel coiled-coil trimer. However, the scaffold was later redesigned as a single peptide chain containing three α-helices connected by linker regions. The new structure allows for concentration-independent assembly and cost-effective scaling in bacterial expression systems.
The three α-helices (A, B, and C) were designed to remain stable even when some residues are modified. Residues in the groove between helices A and C can be modified to bind convex targets, while residues on the outside of helix C can be modified to bind concave protein targets. There are currently 3 libraries containing 1.0 to 1.7 × 108 variations each that can be screened using phage display for target affinity.
The standard Alphabody scaffold contains three α-helices, composed of four heptad repeats (stretches of 7 residues) each, connected via glycine/serine-rich linkers. The standard heptad sequence is "IAAIQKQ". Alanines are associated with α-helix formation, while isoleucines are known to induce coiled-coil formation. Specific residues on the A and C helices can be modified to bind targets, but only variants that retain thermostability are used for further research.
Specifically, the reference scaffold structure is N–HRS1–L1–HRS2–L2–HRS3–C.
HRS = IEEIQKQIAAIQKQIAAIQKQIYRM; L = TGGSGGGSGGGSGGGSGMS
The linker length is long enough to allow helices to fold in parallel or anti-parallel conformations, but experiments suggest only anti-parallel folding occurs.
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Alphabody
Alphabodies, also known as Cell-Penetrating Alphabodies or CPAB for short, are small 10 kDa proteins engineered to bind to a variety of antigens. Despite their name, they are not structurally similar to antibodies, which makes them a type of antibody mimetic. Alphabodies are different from many other antibody mimetics in their ability to reach and bind to intracellular protein targets. Their single chain alpha-helical structure is designed by computer modelling, inspired by naturally existing coiled-coil protein structures. Alphabodies are being developed by the Belgian biotechnology company Complix N.V. as potential new pharmaceutical drugs against cancer and autoimmune disease. In 2012, a collaboration agreement was signed with Monsanto to develop the technology for agricultural applications as well.
Alphabodies are developed as scaffolds with a set of amino acid residues that can be modified to bind protein targets, while maintaining correct folding and thermostability.
The Alphabody scaffold is computationally designed based on coiled-coil structures, but it has no known counterpart in nature. Initially, the scaffold was made of three peptides that associated non-covalently to form a parallel coiled-coil trimer. However, the scaffold was later redesigned as a single peptide chain containing three α-helices connected by linker regions. The new structure allows for concentration-independent assembly and cost-effective scaling in bacterial expression systems.
The three α-helices (A, B, and C) were designed to remain stable even when some residues are modified. Residues in the groove between helices A and C can be modified to bind convex targets, while residues on the outside of helix C can be modified to bind concave protein targets. There are currently 3 libraries containing 1.0 to 1.7 × 108 variations each that can be screened using phage display for target affinity.
The standard Alphabody scaffold contains three α-helices, composed of four heptad repeats (stretches of 7 residues) each, connected via glycine/serine-rich linkers. The standard heptad sequence is "IAAIQKQ". Alanines are associated with α-helix formation, while isoleucines are known to induce coiled-coil formation. Specific residues on the A and C helices can be modified to bind targets, but only variants that retain thermostability are used for further research.
Specifically, the reference scaffold structure is N–HRS1–L1–HRS2–L2–HRS3–C.
HRS = IEEIQKQIAAIQKQIAAIQKQIYRM; L = TGGSGGGSGGGSGGGSGMS
The linker length is long enough to allow helices to fold in parallel or anti-parallel conformations, but experiments suggest only anti-parallel folding occurs.