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The Tat inhibitor dCA locks HIV in persistent latency. This drug class enables block-and-lock functional cure approaches, aimed at reducing residual viremia during therapy and limiting viral rebound. dCA may also have additional therapeutic benefits since Tat is also neurotoxic. Unfortunately, Tat inhibitors are not clinically available. We generated chemical derivatives and rationalized binding to an active and specific Tat conformer. dCA features required for Tat inhibition are distinct from features needed for inhibition of cyclin-dependent kinase 8 (CDK8), the only other known target of dCA. Furthermore, knockdown of CDK8 did not impact dCA\u2019s activity on HIV-1 transcription. Binding of dCA to Tat\u2019s basic domain altered the local protein environment and rendered Tat more resistant to proteolytic digestion. dCA locks a transient conformer of Tat, blocking functions dependent on its basic domain, namely its ability to amplify viral transcription. Our results define dCA\u2019s mode of action, support structure-based-design strategies targeting Tat, and provide valuable information for drug development around the dCA pharmacophore.<\/jats:p>","DOI":"10.1128\/mbio.02662-18","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T12:11:21Z","timestamp":1549282281000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":87,"title":["Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat"],"prefix":"10.1128","volume":"10","author":[{"given":"Sonia","family":"Mediouni","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Chinthalapudi","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and 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