**5. Conclusion**

*Parasitology and Microbiology Research*

As described in the earlier section, Villa et al. designed and synthesized peptidomimetics belonging to 1,2,3-triazoles, specifically 1,4-disubstituted 1,2,3-triazoles. These compounds mimicked the contacts made by PfAtg3 template structure containing the residues W-L-L-P, as this template was shown to have the majority of interactions with PfAtg8. Of the four compounds synthesized, compound 2 (C2) exhibited prominent inhibition (IC50–3.8 μM) in vitro, while C1 had better inhibitory effects in vivo [37]. Natural inhibitors of proteases are one of the best studies substrate groups in malaria as they are highly specific, stable, and reversible. *Plasmodium spp.* contain inhibitors of cysteine proteases (ICPs) and endogenous macromolecular inhibitors, which regulate the activity of cysteine proteases. Orthologs of ICPs are also observed in other apicomplexan groups such as *Trypanosoma cruzi*, whose ICP is called as chagasin [43]. Chagasin was shown to potently bind to the active site of both falcipains, FP2 and FP3. More importantly, three loop regions termed BC-, DE-, and FG loops

**98**

**Figure 5.**

*Crucial interactions between falcipains and ICPs chagasin and falstatin. (A) Solved structure of FP2 and chagasin in that the ICP bound to the active site of falcipain and that (B) three loops BD, DE, and FG are involved in this interactions. (C, D) mutagenesis studies indicated that just the BC loop of falstatin was sufficient for inhibiting both FP2 (C) and FP3 (D), respectively. Adapted and modified from [44, 45].*

Protein-protein interactions play roles of utmost importance in the growth and survival of any organism. Thus, focused targeting of such interactions specific to parasite can help produce robust and effective drugs. Recent research has indicated a renewed interest in targeting PPIs in the field of malaria. Various PPIs in pathways essential for parasite survival, erythrocyte invasion/egress, drug resistance, and others have been elucidated. These new classes of peptidomimetic compounds would form the future defense against an ever-increasing resistant parasite threat. Targeting PPIs offers several advantages over active site inhibition as 'hot-spots' are more flexible as compared to the active site and thus can be more selective in terms of drug interactions. In contrary to active site, the interactions at allosteric sites and exosites in an enzyme occur away from the active site; thus they tend to fall under less drug pressure and are less likely to develop resistance.

### **Acknowledgements**

We thank NIMR, New Delhi, for providing basic infrastructure facilities. We also thank Indian Council of Medical Research for providing fellowship assistance to Mr. Rahul (45/16/2019-Bio/BMS).

## **Conflict of interest**

The authors declare no conflict of interest.
