![]() Therefore, the design and synthesis of cysteine protease inhibitors (CPIs) holds significant value in medicine and biotechnology. Their suitability as a potential drug target for antiparasitic chemotherapy is very well validated. ![]() PLCPs in parasites are also known for their indispensable roles in parasite growth and cell differentiation, signalling and host invasion. Cathepsins have been implicated in the development and progression of many diseases involving abnormal protein turnover and thus, are popular therapeutic targets for several diseases like arthritis, osteoporosis, atherosclerosis, cancer, inflammatory, and immune-related diseases. Mammalian counterparts of PLCPs are lysosomal cysteine cathepsins (cathepsin B, H, L, C, X, F, O, V) that are involved in normal cellular protein degradation and turnover in mammals. This study also demonstrates the relevance of ultrastable peptide-based scaffolds for the development of novel inhibitors via grafting. The outcomes of this study pave the way for further modifications of the Mco-CPI design for realizing its full potential in therapeutics. To conclude, in this McoTI-II analogue, the specificity had been successfully redirected towards C1A cysteine proteases while retaining the moderate affinity. Furthermore, molecular dynamics simulation of the Mco-CPI–papain complex validated the interaction as stable. Using an in silico approach based on homology modelling, protein–protein docking, the calculation of the free-energy of binding, the mechanism of inhibition of Mco-CPI against representative C1A cysteine proteases (papain and cathepsin L) was validated. The recombinantly expressed Mco-CPI protein was able to bind with micromolar affinity to papain and showed remarkable thermostability owing to the formation of multi-disulphide bonds. This was accomplished by grafting the cystatin first hairpin loop conserved motif (QVVAG) onto loop 1 of the ultrastable cyclic peptide scaffold McoTI-II. Here, we report a novel design of a re-engineered chimera inhibitor Mco-cysteine protease inhibitor (CPI) to inhibit the activity of C1A cysteine proteases. Novel approaches towards the development of their inhibitors can open new avenues in translational medicine. Clan C1A or ‘papain superfamily’ cysteine proteases are key players in many important physiological processes and diseases in most living systems.
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