Insights from structure-activity relationships and the binding mode of peptidic α-ketoamide inhibitors of the malaria drug target subtilisin-like SUB1.

Autor: Legru A; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France., Batista FA; Structural Microbiology, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Puszko AK; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France., Bouillon A; Structural Microbiology, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Maurel M; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France., Martinez M; Structural Microbiology, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Ejjoummany A; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France., Ortega Varga L; Structural Bioinformatic, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Adler P; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France., Méchaly A; Cristallography Platform-C2RT, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Hadjadj M; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France., Sosnowski P; Department of Inorganic and Analytical Chemistry, University of Geneva, CH-1211, Geneva, Switzerland., Hopfgartner G; Department of Inorganic and Analytical Chemistry, University of Geneva, CH-1211, Geneva, Switzerland., Alzari PM; Structural Microbiology, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Blondel A; Structural Bioinformatic, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Haouz A; Cristallography Platform-C2RT, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France., Barale JC; Structural Microbiology, UMR3528, Institut Pasteur, CNRS, Université de Paris, Paris, France. Electronic address: jean-christophe.barale@pasteur.fr., Hernandez JF; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Univ Montpellier, ENSCM, Montpellier, France. Electronic address: jean-francois.hernandez@umontpellier.fr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Apr 05; Vol. 269, pp. 116308. Date of Electronic Publication: 2024 Mar 11.
DOI: 10.1016/j.ejmech.2024.116308
Abstrakt: Plasmodium multi-resistance, including against artemisinin, seriously threatens malaria treatment and control. Hence, new drugs are urgently needed, ideally targeting different parasitic stages, which are not yet targeted by current drugs. The SUB1 protease is involved in both hepatic and blood stages due to its essential role in the egress of parasites from host cells, and, as potential new target, it would meet the above criteria. We report here the synthesis as well as the biological and structural evaluation of substrate-based α-ketoamide SUB1 pseudopeptidic inhibitors encompassing positions P4-P2'. By individually substituting each position of the reference compound 1 (MAM-117, Ac-Ile-Thr-Ala-AlaCO-Asp-Glu (Oall)-NH 2 ), we better characterized the structural determinants for SUB1 binding. We first identified compound 8 with IC 50 values of 50 and 570 nM against Pv- and PfSUB1, respectively (about 3.5-fold higher potency compared to 1). Compound 8 inhibited P. falciparum merozoite egress in culture by 37% at 100 μM. By increasing the overall hydrophobicity of the compounds, we could improve the PfSUB1 inhibition level and antiparasitic activity, as shown with compound 40 (IC 50 values of 12 and 10 nM against Pv- and PfSUB1, respectively, IC 50 value of 23 μM on P. falciparum merozoite egress). We also found that 8 was highly selective towards SUB1 over three mammalian serine peptidases, supporting the promising value of this compound. Finally, several crystal 3D-structures of SUB1-inhibitor complexes, including with 8, were solved at high resolution to decipher the binding mode of these compounds.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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