Institute of Biomedical Research, Yunnan University, Chenggong District, Kunming, China
« The HIV-1 maturation inhibitor, EP39, interferes with the dynamic helix-coil equilibrium of the CA-SP1 junction of Gag »
European Journal of Medicinal Chemistry 204 (2020) 112634.https://doi.org/10.1016/j.ejmech.2020.112634 Xiaowei Chen, Pascale Coric, Valery Larue, Serge Turcaud, Xiao Wang,Sylvie Nonin-Lecomte, Serge Bouaziz.
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Xiaowei CHEN, 32, defended her PhD in the « Cibles Thérapeutiques et Conception du Médicament » Laboratory (CiTCoM) UMR 8038 (CNRS, University of Paris, Faculty of Pharmacy). Her work focuses on the maturation of the HIV-1 viral particle. Maturation of human immunodeficiency virus type 1 (HIV-1) particle is initiated by cleavages of the protein precursor Gag by the protease and allows the production of several proteins to form the mature HIV-1. The final cleavage at CA-SP1 junction is the limiting step. The main maturation inhibitor blocks the final cleavage between CA and SP1. Xiaowei CHEN and her collaborators used nuclear magnetic resonance (NMR) to investigate how inhibitors impact the structural and dynamic properties of this cleavage domain. The selected publication describes the helical structure of the SP1 domain under physiological conditions. Polymorphism of the SP1 domain is associated with reduced inhibitor activity in vivo. Binding of the inhibitors disturbs dynamics of this motif leading to an inhibition of the maturation of viral particles by the protease.
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Institute of Biomedical Research, Yunnan University, Chenggong District, Kunming, 650500, Yunnan, China
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Article summary
During the maturation of HIV-1 particle, the Gag polyprotein is cleaved into several proteins by the HIV-1 protease. These proteins rearrange to form infectious virus particles. In this study, the solution structure and dynamics of a monomeric mutated domain encompassing the C-terminal of capsid, the spacer peptide SP1 and the nucleocapsid from Gag was characterized by Nuclear Magnetic Resonance in the presence of maturation inhibitor EP39, a more hydro-soluble derivative of BVM. We show that the binding of EP39 decreases the dynamics of CA-SP1 junction, especially the QVT motif in SP1, and perturbs the natural coil-helix equilibrium on both sides of the SP1 domain by stabilizing the transient alpha helical structure. Our results provide new insight into the structure and dynamics of the SP1 domain and how HIV-1 maturation inhibitors interfere with this domain. They offer additional clues for the development of new second generation inhibitors targeting HIV-1 maturation
