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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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Accessing anti HIV activity through the attenuation of USP18 activity.pdf | Abstract | 65.59 kB | Adobe PDF | View/Open |
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