As a highly attractive drug target, the 3CL-Pro (nsp5) has been functionally and structurally characterized by several groups. Several structures in presence and absence of ligands are available in the PDB (1P9S, 1P9U, 1Q2W, 1UJ1, 1UK2, 1UK3, 1UK4, 1WOF, 1Z1I, 1Z1J, 2A5A, 2A5I, 2A5K, 2AMD, 2AMQ, 2BX3, 2BX4, 2C3S, 2D2D, 1WNP, 2ALV, 2CGG, 2GT7, 2GT8, 2GTB, 2GX4, 2GZ7, 2GZ8, 2GZ9, 2H2Z). The enzyme acts via a general base mechanism, cleaving peptides with a Leu-Gln || (Ser, Ala, Gly) specificity . It comprises of three domains, with the substratebinding site being located in a cleft between the first two domains. Deletion analysis reveals that the N-terminus (particularly the fourth residue), and the C-terminal domain are important for activity, as is its dimerization state that is stabilized by these segments. Intense searches have resulted in a large number of inhibitors with nanomolar to low micromolar affinities. Prominent among them are peptidomimetic esters , anilides , hexachlorophene and its analogues , natural polyphenols , isatin derivatives , Cinanserin (a serotonin antagonist) , interferons , monoclonal antibodies and HIV-protease inhibitors, keto-glutamine analogues, metal (particularly zinc) conjugated compounds , aryl boronic acid compounds, sabadinine , and numerous small molecule inhibitors from high-throughout screens. While most, if not all, of these compounds are directed at the active site, inhibitors which disrupt the dimerization interface are also much sought after. Recently, an octapeptide inhibitor based on the N-terminal sequence of 3CL-Pro was found to inhibit its dimerization thereby proving the potential for peptidomimetics based inhibition approaches. |