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A comprehensive lead optimization campaign was undertaken to develop a novel long-acting NRTTI with the potential for extended-duration dosing for HIV prophylaxis. Broad exploration of nucleoside structure\u2013activity relationship (SAR), leveraging ribose core, periphery, and nucleobase modifications, along with systematic progression of compounds of interest through key in vitro and in vivo studies led to the discovery of MK-8527. MK-8527 is a novel deoxyadenosine analog that is phosphorylated intracellularly to its active triphosphate (TP) form, which inhibits reverse transcription. Iron footprinting and primer extension assays demonstrated that MK-8527-TP inhibits translocation of reverse transcriptase on the primer and template, and this inhibition allows for both immediate and delayed chain termination of reverse transcription. MK-8527 inhibits viral replication in human peripheral blood mononuclear cells (PBMCs), with a half maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) of 0.21 nM. The pharmacokinetic (PK) profile of MK-8527 in rats and rhesus monkeys was characterized by low-to-moderate clearance and volume of distribution, with good oral absorption (57% and 100% in rats and monkeys, respectively). Following oral administration of MK-8527 to monkeys, MK-8527-TP exhibited an intracellular half-life of approximately 48 h in PBMCs, significantly longer than the apparent plasma half-life of the parent compound (approximately 7 h). MK-8527 and MK-8527-TP demonstrated favorable in vitro off-target profiles, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of \u226595 \u00b5M against human DNA polymerases tested, and no off-target activities at 10 \u03bcM against a panel of 114 enzyme and receptor binding assays. Collectively, the potent antiretroviral activity and favorable preclinical PK and off-target profiles make MK-8527 an attractive clinical candidate, and it is currently in clinical trials for once-monthly oral HIV-1 pre-exposure prophylaxis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003308","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T17:24:06Z","timestamp":1756229046000},"page":"e3003308","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["MK-8527 is a novel inhibitor of HIV-1 reverse transcriptase translocation with potential for extended-duration dosing"],"prefix":"10.1371","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-8816","authenticated-orcid":true,"given":"Izzat 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