{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:12Z","timestamp":1792790412215,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,25]]},"group-title":"Microbiology","reference-count":93,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH \/ NIAID","award":["R21AI157362"],"award-info":[{"award-number":["R21AI157362"]}]},{"name":"State of Florida Biomedical Research Program","award":["Bankhead Coley Research Infrastructure grant 23B16"],"award-info":[{"award-number":["Bankhead Coley Research Infrastructure grant 23B16"]}],"id":[{"id":"https:\/\/ror.org\/04x1xkh65","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  We aimed to repurpose the non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) rilpivirine (RPV) as a targeted protein degrader (TPD) of HIV-1 RT. Structure-guided modeling identified a TPD bifunctional linker exit trajectory from RPV that threads the NNRTI entrance channel. Ten RPV analogs (RPV\u2019) with varied warhead-linker attachments retained RT inhibition and antiviral activity, guiding selection of an amide-linked connector for degrader construction. We synthesized Proteolysis Targeting Chimeras (PROTACs) designed to recruit CUL4\n                  <jats:sup>CRBN<\/jats:sup>\n                  and CUL2\n                  <jats:sup>VHL<\/jats:sup>\n                  , alongside adamantyl acetic acid-based Hydrophobic Tags (HyTs). TPDs were evaluated for RT inhibition, virus inhibition, biophysical target engagement, and proteasome-dependent degradation. Some PROTACs showed minimal antiviral activity or limited solubility for our assays, whereas the HyT with a tetraethylene glycol (PEG4) linker (PEG4-Ad) exhibited low-nanomolar potency to suppress HIV-1 replication and acceptable solubility. PEG4-Ad reduced RT levels in a proteasome-dependent manner without cytotoxicity but did not exhibit superior potency against RPV resistance mutations. MD simulations suggested that PEG4 linkers maximize episodic exposure of the hydrophobic tag, consistent with PEG4-Ad efficacy. These data highlight the promise\u2014and constraints\u2014of antiviral degraders, indicating that linker-controlled hydrophobic tag exposure and subcellular target accessibility may be critical design parameters for prospective therapeutics.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.753933","type":"posted-content","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:35:29Z","timestamp":1790393729000},"source":"Crossref","is-referenced-by-count":0,"title":["Performance of Rilpivirine-Based Hydrophobic Tags and PROTACs Directed Against HIV-1 Reverse Transcriptase"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2455-3606","authenticated-orcid":false,"given":"Ferdinand K.","family":"Amanor","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, AL, 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