{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:22:47Z","timestamp":1760232167383,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,16]],"date-time":"2022-10-16T00:00:00Z","timestamp":1665878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 AI104416","HHSN272201400002C"],"award-info":[{"award-number":["R01 AI104416","HHSN272201400002C"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH\/NIAID","award":["R01 AI104416","HHSN272201400002C"],"award-info":[{"award-number":["R01 AI104416","HHSN272201400002C"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>We earlier reported substantial progress in designing gp120 antagonists. Notably, we discovered that NBD-14189 is not only the most active gp120 antagonist but also shows antiviral activity against HIV-1 Reverse Transcriptase (RT). We also confirmed its binding to HIV-1 RT by X-ray crystallography. The dual inhibition is highly significant because, intriguingly, this compound bridges the dNTP and NNRTI-binding sites and inhibits the polymerase activity of isolated RT in the enzymatic assay. This novel finding is expected to lead to new avenues in designing a novel class of HIV-1 dual inhibitors. Therefore, we needed to advance this inhibitor to preclinical assessment. To this end, we report the pharmacokinetics (PK) study of NBD-14189 in rats and dogs. Subsequently, we assessed the toxicity and therapeutic efficacy in vivo in the SCID-hu Thy\/Liv mouse model. The PK data indicated a favorable half-life (t1\/2) and excellent oral bioavailability (%F = 61%). NBD-14189 did not show any measurable toxicity in the mice, and treatment reduced HIV replication at 300 mg\/kg per day in the absence of clear evidence of protection from HIV-mediated human thymocyte depletion. The data indicated the potential of this inhibitor as an anti-HIV-1 agent and needs to be assessed in a non-human primate (NHP) model.<\/jats:p>","DOI":"10.3390\/v14102268","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T05:08:02Z","timestamp":1665983282000},"page":"2268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparative Pharmacokinetics of a Dual Inhibitor of HIV-1, NBD-14189, in Rats and Dogs with a Proof-of-Concept Evaluation of Antiviral Potency in SCID-hu Mouse Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-6044","authenticated-orcid":false,"given":"Cheryl A.","family":"Stoddart","sequence":"first","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, CA 94110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Curreli","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling & Drug Design, New York Blood Center, Lindsley F. Kimball Research Institute, 310 E 67th Street, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Horrigan","sequence":"additional","affiliation":[{"name":"Noble Life Sciences Inc., Woodbine, MD 21784, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9815-9866","authenticated-orcid":false,"given":"Andrea","family":"Altieri","sequence":"additional","affiliation":[{"name":"EDASA Scientific srls, Via Stingi 37, 66050 San Salvo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander V.","family":"Kurkin","sequence":"additional","affiliation":[{"name":"EDASA Scientific srls, Via Stingi 37, 66050 San Salvo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2761-0506","authenticated-orcid":false,"given":"Asim K.","family":"Debnath","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling & Drug Design, New York Blood Center, Lindsley F. Kimball Research Institute, 310 E 67th Street, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1021\/acs.jmedchem.9b02149","article-title":"Preclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation","volume":"63","author":"Curreli","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.ejmech.2018.04.062","article-title":"Structure-based lead optimization to improve antiviral potency and ADMET properties of phenyl-1H-pyrrole-carboxamide entry inhibitors targeted to HIV-1 gp120","volume":"154","author":"Curreli","year":"2018","journal-title":"Eur. J. Med. 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