{
  "abstract": "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') 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 CUL4CRBN and CUL2VHL, 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 - and constraints - of antiviral degraders, indicating that linker-controlled hydrophobic tag exposure and subcellular target accessibility may be critical design parameters for prospective therapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "F. K. Amanor"
    },
    {
      "name": "G. D. Clements"
    },
    {
      "name": "R. Khurshid"
    },
    {
      "name": "A. F. Howard"
    },
    {
      "name": "D. M. Soto-Martinez"
    },
    {
      "name": "C. Barkley"
    },
    {
      "name": "Z. Yang"
    },
    {
      "name": "K. Gyawali"
    },
    {
      "name": "J. C. Kappes"
    },
    {
      "name": "R. C. Reynolds"
    },
    {
      "name": "S. C. Schürer"
    },
    {
      "name": "T. S. Snowden"
    },
    {
      "affs": [
        0
      ],
      "name": "C. Ochsenbauer"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/faxmazpa8wvv0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.753933",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753933v1.full",
  "id": "faxmazpa8wvv0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753933v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "microbiology"
    ],
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7214391265",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753933v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/faxmazpa8wvv0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:37Z",
      "native_id": "10.64898/2026.09.24.753933",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.24.753933v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:microbiology",
      "subfield": "microbiology"
    }
  ],
  "title": "Performance of Rilpivirine-Based Hydrophobic Tags and PROTACs Directed Against HIV-1 Reverse Transcriptase",
  "title_text": "Performance of Rilpivirine-Based Hydrophobic Tags and PROTACs Directed Against HIV-1 Reverse Transcriptase",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:37Z",
  "url": "https://research.draconitic.com/paper/faxmazpa8wvv0",
  "venue": "bioRxiv",
  "versions": []
}