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While current therapies keep the virus at bay\u2014suppressing viral loads and minimizing risks of transmission\u2014viral mutations that confer drug resistance are still a significant problem. It would, therefore, be advantageous to have therapies that address viral targets that are highly conserved and critical for viral replication. One such option is \u03c8RNA. This region of RNA serves as the recognition site for the NCp7 viral protein. The binding of NCp7 to \u03c8RNA guides the packaging of intact viral RNA into nascent daughter virions. Thwarting this process leads to virions that incorporate nonfunctional RNAs and are not infectious. Based on prior studies, we designed, synthesized, and tested a library of nonproteinogenic tetrapeptides to target stem\u2010loop elements of \u03c8RNA known to interact with NCp7. Peptides incorporating aza\u2010indole (tryptophan\u2010like) amino acids displayed considerable anti\u2010HIV and trophic\u2010specific activity yet failed to inhibit packaging. Instead, our best analog (IC\n                    <jats:sub>50<\/jats:sub>\n                    2.84\u2009\u00b5M) was a potent protease inhibitor, comparable to FDA\u2010approved Lopinavir (1.44\u2009\u00b5M) and Nelfinavir (1.54\u2009\u00b5M). Together, our studies demonstrate the perils that can accompany early\u2010phase discovery efforts, and the serendipitous findings that can sometimes result. They also showcase the power of unnatural tryptophan mimics to imbue unique antiretroviral structure\u2013activity.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70372","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T07:37:22Z","timestamp":1783669042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>A Priori<\/i>\n                    Design, Combinatorial Synthesis, and Assessment of an Antipackaging Peptide Against Human Immunodeficiency Virus 1: Functional Role of Unnatural Trp Mimetics and Serendipitous Discovery of a Protease Inhibitor"],"prefix":"10.1002","volume":"21","author":[{"given":"Jacob R.","family":"Immel","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry University of Kansas  Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Hsuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Kansas  Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"McDonald","sequence":"additional","affiliation":[{"name":"COBRE CBID Infectious Disease Assay Development Core University of Kansas  Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Roy","sequence":"additional","affiliation":[{"name":"COBRE CBID Infectious Disease Assay Development Core University of Kansas  Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Johnson","sequence":"additional","affiliation":[{"name":"Computational Chemical Biology Core University of Kansas  Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4205-4459","authenticated-orcid":false,"given":"Steven","family":"Bloom","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Kansas  Lawrence Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12981-025-00745-5"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.118190"},{"key":"e_1_2_9_4_1","first-page":"111","article-title":"Update of the Drug Resistance Mutations in HIV\u20101","volume":"27","author":"Wensing A. 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