ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development
Siddhartha Mishra,
Nipun Malhotra,
Benoît Laleu,
Soumyananda Chakraborti,
Manickam Yogavel,
Amit Sharma
Affiliations
Siddhartha Mishra
Molecular Medicine – Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India; ICMR-National Institute of Malaria Research (NIMR), Dwarka, New Delhi 110077, India; Academy of Scientific and Innovative Research (AcSIR), UP, India
Nipun Malhotra
Molecular Medicine – Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India
Benoît Laleu
Medicines for Malaria Venture (MMV), International Center Cointrin (ICC), Route de Pré-Bois 20, 1215 Geneva, Switzerland
Soumyananda Chakraborti
ICMR-National Institute of Malaria Research (NIMR), Dwarka, New Delhi 110077, India; Academy of Scientific and Innovative Research (AcSIR), UP, India
Manickam Yogavel
Molecular Medicine – Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India
Amit Sharma
Molecular Medicine – Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India; Corresponding author
Summary: 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 Plasmodium falciparum 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 [EC50]) selectivity for the parasite. The macromolecular structures of PfPRS with L95 and L97 in complex with L-pro reveal their binding modes and catalytic site malleability. Arg401 of PfPRS 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.
