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Inhibition of Plasmodium falciparum Lysyl‐tRNA synthetase via a piperidine‐ring scaffold inspired Cladosporin analogues

DOI: 10.1002/cbic.202100212 DOI Help

Authors: Palak Babbar (International Centre for Genetic Engineering and Biotechnology) , Mizuki Sato (Tohoku Pharmaceutical University) , Yogavel Manickam (International Centre for Genetic Engineering and Biotechnology) , Siddhartha Mishra (International Centre for Genetic Engineering and Biotechnology) , Karl Harlos (University of Oxford) , Swati Gupta (International Centre for Genetic Engineering and Biotechnology) , Suhel Parvez (Jamia Hamdard) , Haruhisa Kikuchi (Keio University) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chembiochem

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 19946

Abstract: Plasmodium falciparum lysyl tRNA synthetase ( Pf KRS) represent a promising therapeutic anti‐malarial target. Cladosporin, a tool compound was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with x‐ray crystallography reveals compounds to be of moderate potency. Co‐crystals of Cla‐B and Cla‐C with PfKRS reveals key atomic configurations that allow drug binding to, and inhibition of the enzyme. Collectively, these piperidine ring scaffold inhibitors lays a framework for further structural editing and functional modifications of cladosporin scaffold to obtain a potent lead.

Journal Keywords: Anti-malaria; Cladosporin; Diastereomers; Co-crystal; Drug development

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 11/05/2021 10:32

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Disease in the Developing World Drug Discovery Infectious Diseases Structural biology Chemistry Biochemistry Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)