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HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor (Vif). Vif causes proteasomal degradation of A3G and A3F proteins (A3G\/F) in HIV-producing cells to ensure infectivity of virions subsequently released from these cells. Here, we optimized a lead compound reported previously to boost cellular levels of A3G. The modified analogs designed, synthesized, and evaluated here inhibit cell-mediated post-translational degradation of A3G\/F, whether Vif is present or not. This increases A3G\/F incorporation into Vif-positive virions to decrease viral infectivity. The compounds and processes described here can facilitate the development of new anti-HIV therapeutics whose host-targeted effect may not be evaded by resistance-conferring mutations in HIV Vif.<\/jats:p>","DOI":"10.3390\/v17040514","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T08:21:41Z","timestamp":1743495701000},"page":"514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design and Characterization of Inhibitors of Cell-Mediated Degradation of APOBEC3G That Decrease HIV-1 Infectivity"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0862-2237","authenticated-orcid":false,"given":"Aubrey M.","family":"Sawyer","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1457-0990","authenticated-orcid":false,"given":"Cristina C.","family":"Vaca","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Northwestern University Weinberg College of Arts and Sciences, Evanston, IL 60208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7140-7049","authenticated-orcid":false,"given":"Isabelle","family":"Clerc","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8676-224X","authenticated-orcid":false,"given":"Joshua","family":"Craft","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Hudson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebl K.","family":"Scholt\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4180-5051","authenticated-orcid":false,"given":"Gary E.","family":"Schiltz","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Northwestern University Weinberg College of Arts and Sciences, Evanston, IL 60208, USA"},{"name":"Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA"},{"name":"Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meejeon","family":"Roh","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chisu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9653-5987","authenticated-orcid":false,"given":"Richard T.","family":"D\u2019Aquila","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1073\/pnas.1914183116","article-title":"Retroviruses drive the rapid evolution of mammalian APOBEC3 genes","volume":"117","author":"Ito","year":"2020","journal-title":"Proc. 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