Latest developments in small molecule inhibitors of cysteine protease B as antileishmanial drugs

Leishmaniasis is a neglected tropical disease, transmitted by the bite of infected female sandflies and affecting the poor population. Current pharmacotherapy has remained largely unchanged for decades, and there are parasitic strains resistant to these conventional treatments. Thus, there is an urgent need to identify molecular targets to guide the rational design of new drugs. Thus, cysteine protease B (CPB) emerges as a promising target due to its roles in pathogenesis, virulence, and in modulating the host immune response. Given this potential, this review presents recent advances in CPB inhibitors, examining scaffolds, their structure-activity relationships (SARs), and the structural elements that confer selectivity for the parasitic target. Aziridine analogs and dipeptidyl nitriles stand out, and the SAR studies presented here indicate that structural modifications in the P1, P2, and P3 binding subsites influence compound affinity, thereby optimizing molecular fit in the enzyme. The stereochemical configuration (S,S) of the inhibitors is also essential for potency. Regarding selectivity, the Tyr210 residue is present in CPB but not in human cathepsin L. Taken together, these structural and mechanistic findings offer new perspectives for advancing medicinal chemistry targeting CPB, in the development of safer, more selective, and more effective antileishmanial agents.