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DC Field | Value | Language |
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dc.contributor.author | Lester T Sigauke | en_US |
dc.contributor.author | Jonathan Bvunzawabaya | en_US |
dc.contributor.author | Gabrielle Le Bury | en_US |
dc.contributor.author | Godwin A. Dziwornu | en_US |
dc.contributor.author | Saikat Boliar | en_US |
dc.contributor.author | David W Gludish | en_US |
dc.contributor.author | David G Russell | en_US |
dc.contributor.author | Krishna Govender | en_US |
dc.contributor.author | Grace Mugumbate | en_US |
dc.contributor.author | Nyaradzo Chigorimbo-Murefu | en_US |
dc.date.accessioned | 2024-08-26T13:01:19Z | - |
dc.date.available | 2024-08-26T13:01:19Z | - |
dc.date.issued | 2024-06-28 | - |
dc.identifier.uri | https://cris.library.msu.ac.zw//handle/11408/6253 | - |
dc.description.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. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Cold Spring Harbor Laboratory | en_US |
dc.relation.ispartof | bioRxiv | en_US |
dc.subject | anti-HIV | en_US |
dc.subject | USP18 | en_US |
dc.subject | molecular dynamic 3 simulations | en_US |
dc.subject | free-energy profiling | en_US |
dc.subject | multi-cellular 4 inhibition | en_US |
dc.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 | en_US |
dc.type | preprint | en_US |
dc.identifier.doi | https://doi.org/10.1101/2024.06.23.600290 | - |
dc.contributor.affiliation | Division of Medical Virology, Department of Pathology, University of Cape Town, Rondebosch, South Africa | en_US |
dc.contributor.affiliation | Department of Chemical Sciences, Faculty of Science and Technology, Midlands State University, Gweru, Zimbabwe | en_US |
dc.contributor.affiliation | Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America | en_US |
dc.contributor.affiliation | Department of Chemistry, University of Cape Town, Rondebosch, South Africa | en_US |
dc.contributor.affiliation | Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America | en_US |
dc.contributor.affiliation | Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America | en_US |
dc.contributor.affiliation | Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America | en_US |
dc.contributor.affiliation | Department of Chemical Sciences, University of Johannesburg, Doornfontein Campus, Johannesburg, South Africa | en_US |
dc.contributor.affiliation | Department of Chemical Sciences, Faculty of Science and Technology, Midlands State University, Gweru, Zimbabwe | en_US |
dc.contributor.affiliation | 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 | en_US |
dc.description.startpage | 1 | en_US |
dc.description.endpage | 49 | en_US |
item.grantfulltext | open | - |
item.fulltext | With Fulltext | - |
item.cerifentitytype | Publications | - |
item.languageiso639-1 | en | - |
item.openairetype | preprint | - |
item.openairecristype | http://purl.org/coar/resource_type/c_816b | - |
Appears in Collections: | Research Papers |
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File | Description | Size | Format | |
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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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