Please use this identifier to cite or link to this item: https://cris.library.msu.ac.zw//handle/11408/6253
Title: Accessing anti-HIV activity through the attenuation of USP18 activity: novel insights from molecular dynamic simulations, free-energy profiling, and multi-cellular inhibition assays
Authors: Lester T Sigauke
Jonathan Bvunzawabaya
Gabrielle Le Bury
Godwin A. Dziwornu
Saikat Boliar
David W Gludish
David G Russell
Krishna Govender
Grace Mugumbate
Nyaradzo Chigorimbo-Murefu
Division of Medical Virology, Department of Pathology, University of Cape Town, Rondebosch, South Africa
Department of Chemical Sciences, Faculty of Science and Technology, Midlands State University, Gweru, Zimbabwe
Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
Department of Chemistry, University of Cape Town, Rondebosch, South Africa
Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
Department of Chemical Sciences, University of Johannesburg, Doornfontein Campus, Johannesburg, South Africa
Department of Chemical Sciences, Faculty of Science and Technology, Midlands State University, Gweru, Zimbabwe
Division of Medical Virology, Department of Pathology, University of Cape Town, Rondebosch, South Africa; International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
Keywords: anti-HIV
USP18
molecular dynamic 3 simulations
free-energy profiling
multi-cellular 4 inhibition
Issue Date: 28-Jun-2024
Publisher: Cold Spring Harbor Laboratory
Abstract: The feasibility of achieving anti-HIV activity from the attenuation of USP18 activity was explored for the first time. A cheminformatic survey demonstrated that the current known USP18 isopeptidase inhibitors are derivatives of a bis-aryl pyranone scaffold that possesses undesirable toxicity profiles. Molecular modelling approaches applied to these active bis-aryl pyranones isolated the likely mechanism that perturbs the isopeptidase activity of USP18. Molecular dynamic simulations and free-energy profiling showed that induced-fit effects on the catalytic triad and the IBB-1 domain residues of USP18 drive a reversible non-competitive isopeptidase inhibition mechanism. Proof-of-concept multi-cellular HIV inhibition assays demonstrate the utility of achieving anti-HIV-1 activity from attenuating the activity of USP18 using small molecules. This study motivates for the pursuit of scaffolds that target the allosteric site of USP18, fine-tuning the IFN response as a strategy to enhance the natural control mechanisms that lead to an antiviral state potentially curing viral infection.
URI: https://cris.library.msu.ac.zw//handle/11408/6253
Appears in Collections:Research Papers

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