Academic Journal
Insights from structure-activity relationships and the binding mode of peptidic α-ketoamide inhibitors of the malaria drug target subtilisin-like SUB1
| العنوان: | Insights from structure-activity relationships and the binding mode of peptidic α-ketoamide inhibitors of the malaria drug target subtilisin-like SUB1 |
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| المؤلفون: | Legru, Alice, Batista, Fernando, Puszko, Anna, Bouillon, Anthony, Maurel, Manon, Martinez, Mariano, Ejjoummany, Abdelaziz, Ortega Varga, Laura, Adler, Pauline, Mechaly, Ariel, E, Hadjadj, Margot, Sosnowski, Piotr, Hopfgartner, Gérard, Alzari, Pedro, M., Blondel, Arnaud, Haouz, Ahmed, Barale, Jean-Christophe, Hernandez, Jean-François |
| المساهمون: | Institut des Biomolécules Max Mousseron Pôle Chimie Balard (IBMM), Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Bioinformatique structurale - Structural Bioinformatics, Cristallographie (Plateforme) - Crystallography (Platform), Université de Genève = University of Geneva (UNIGE), This work was supported by Institut Carnot Chimie Balard (FO-ICCB-M1-08 V01), Agence Nationale de la Recherche (ANR-19-CE18-0010-01, including fellowship to FB, PA, AKP, LOV and AE). This project has also received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement SUBUN N◦ 898512 H2020-MSCA-IF-2019 (AKP). A. Bouillon and M. Martinez have been supported by Agence Nationale pour la Recherche (ANR-11-RPIB-002). LOV has also been supported by Agence Nationale pour la Recherche (ANR-17-CE11-0030) and by the “URGENCE COVID-19” fundraising campaign of Institut Pasteur., We thank Mr Pierre Sanchez (IBMM, Montpellier, France) for mass spectrometry analyses. We thank the staff of the Crystallography core facility at the Institut Pasteur for carrying out robot-driven crystalliza- tion screenings. We acknowledge ESRF and SOLEIL for provision of synchrotron radiation facilities and we thank the staffs of the ID29, ID30 and Proxima-1 beamlines for support during data collection. We are grateful to the healthy volunteers for their contribution to the study and thank the staff, particularly H´el`ene Laude, Blanca Liliana Perlaza, Emmanuel Roux, Dorian Cheval, Linda Sangari and Sophie Vacant of ICAReB-Clin and ICAReB-biobank of the CRBIP (BioResource Center) from the Medical Direction at Institut Pasteur for managing the visits of healthy volunteers and for preparing and providing the human blood samples used to cultivate P. falciparum., ANR-17-CE11-0030,NICOFIVE,Découverte de modulateurs allostériques ciblant les récepteurs nicotiniques alpha5(2017), ANR-19-CE18-0010,SPIM,Synthèse, biologie et structure pour guider l'optimisation d'Inhibiteurs de la peptidase SUB1 de Plasmodium, une cible potentielle pour le traitement du paludisme(2019), ANR-11-RPIB-0002,MaPI,Développement d'un composé "leader" à l'origine d'une nouvelle génération d'anti-paludiques: une approche multi-cibles(2011) |
| المصدر: | ISSN: 0223-5234. |
| بيانات النشر: | HAL CCSD Elsevier |
| سنة النشر: | 2024 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | Structure activity relationships, Malaria, SAR, crystal structures, SUB1 inhibitors, Pseudopeptides, a-ketoamides, [SDV]Life Sciences [q-bio], [CHIM]Chemical Sciences |
| الوصف: | International audience ; 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 a-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)-NH2), we better characterized the structural determinants for SUB1 binding. We first identified compound 8 with IC50 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 (IC50 values of 12 and 10 nM against Pv-and PfSUB1, respectively, IC50 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/38503166; PUBMED: 38503166 |
| DOI: | 10.1016/j.ejmech.2024.116308 |
| الاتاحة: | https://hal.science/hal-04727940 https://hal.science/hal-04727940v1/document https://hal.science/hal-04727940v1/file/Legru-Batista_Manuscrit_R.pdf https://doi.org/10.1016/j.ejmech.2024.116308 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.BAEBD015 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ejmech.2024.116308 |
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