Small protein inhibitors of serine proteases can form reversible complexes with the target protease by thermodynamic terms. Although no covalent bonds are formed between the two proteins, the binding affinity can be so high that the interaction is actually irreversible. These tight-binding inhibitors fall into two broad categories: the canonical and noncanonical inhibitors. For years, Creative Biolabs has consistently and effectively supported the anti-complement therapy industry with a unique range of products and related services. We provide biotherapeutics development strategies for serine protease inhibitors including canonical and noncanonical protein inhibitors.
Small Protein Inhibitors
The canonical and noncanonical inhibitors both block the active site of the inhibited enzyme. The canonical inhibitors are typically small (shorter than 100 amino acids) proteins or domains of mosaic protein with different scaffolds but with an exposed inhibitory loop that always shows the same (canonical) main-chain conformation. Such inhibitors follow the standard Laskowski mechanism. This tight lock and key protein-protein interactions involve antiparallel beta-sheet. The unconventional inhibitors cannot mimic the substrate. The N-terminal segment of the inhibitor binds to the active site of the protease, forming a short parallel beta-sheet. The most striking feature of these inhibitors is that they form extra extensive secondary interactions outside the active site, which results in a very high affinity.
Canonical Inhibitors
Canonical inhibitors are promising candidates for developing highly specific serum serine protease inhibitors for use in basic and pharmaceutical applications. Canonical inhibitors contain proteins of 14 to about 200 amino acid residues and are widely distributed in virtually all organisms. A large number of canonical inhibitors that have been described are isolated from various cells, tissues, and organisms. They accumulate abundantly in avian eggs, plant seeds and various body fluids. Typical protein inhibitors do not form a single group but can be divided into different families. In all known inhibitor structures, the segment responsible for protease inhibition (the protease-binding loop) always has a similar, typical conformation. This convex, extended and solvent-exposed loop is highly complementary to the concave active site of the enzyme.
Classification of Canonical Inhibitors
Based on the disulfide bond topography, the location of the reactive site, and sequence homology, canonical inhibitors can be divided into 18 inhibitor families. Almost all families have a definite crystal and/or solution structure. Since inhibitors are small, rigid and stable, these structures are usually determined with high resolution and high accuracy. In addition, the serine protease and enzyme inhibitor complexes readily crystallize, often providing high-resolution data. A wide range of structural information is also available for protease inhibitor complexes. The global structures of proteins that represent different families of inhibitors are quite different. In most cases, they contain pure beta-sheet or mixed alpha/beta proteins, which can also be helical or irregular proteins rich in disulfide cross-links.
As one of the most highly respected drug discovery and antibody development laboratories in the world, Creative Biolabs has been helping customers all over the world make fast and effective biotherapeutics development decisions for decades. We provide biotherapeutics development strategies for serine protease inhibitors including serpins, macroglobulins, and other small protein inhibitors. Our scientists, technicians and regulatory experts are committed to assisting your research with our complement-based R&D services. Please contact us for more information and a detailed quote.
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