ATP Mimetics Targeting Prolyl-tRNA Synthetases As a New Avenue for Antimalarial Drug Development

Overview

Journal iScience

Publisher Cell Press

Date 2024 Aug 6

PMID 39104570

Authors

Siddhartha Mishra

Nipun Malhotra

Benoit Laleu

Soumyananda Chakraborti

Manickam Yogavel

Amit Sharma

Affiliations

Soon will be listed here.

Abstract

The prolyl-tRNA synthetase (PRS) is an essential enzyme for protein translation and a validated target against malaria parasite. We describe five ATP mimetics (L95, L96, L97, L35, and L36) against PRS, exhibiting enhanced thermal stabilities in co-operativity with L-proline. L35 displays the highest thermal stability akin to halofuginone, an established inhibitor of PRS. Four compounds exhibit nanomolar inhibitory potency against PRS. L35 exhibits the highest potency of ∼1.6 nM against asexual-blood-stage (ABS) and ∼100-fold (effective concentration [EC]) selectivity for the parasite. The macromolecular structures of PRS with L95 and L97 in complex with L-pro reveal their binding modes and catalytic site malleability. Arg401 of PRS oscillates between two rotameric configurations when in complex with L95, whereas it is locked in one of the configurations due to the larger size of L97. Harnessing such specific and selective chemical features holds significant promise for designing potential inhibitors and expediting drug development efforts.

Citing Articles

Rational design of 2-chromene-based antiphytovirals that inhibit virion assembly by outcompeting virus capsid-RNA interactions.

Yang X, Liu D, Wei C, Li J, Zhao C, Tian Y iScience. 2024; 27(11):111210.

PMID: 39555397 PMC: 11565046. DOI: 10.1016/j.isci.2024.111210.

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