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Using structure\u2010based design, we incorporated an unprecedented 6\u20105\u20105\u2010ring\u2010fused crown\u2010like tetrahydropyranofuran as the P2\u2010ligand, a cyclopropylaminobenzothiazole as the P2\u2032\u2010ligand, and a 3,5\u2010difluorophenylmethyl group as the P1\u2010ligand. The resulting inhibitor <jats:bold>5<\/jats:bold> exhibited exceptional HIV\u20101 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC<jats:sub>50<\/jats:sub> values in the picomolar range against a wide panel of highly multidrug\u2010resistant HIV\u20101 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug\u2010resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high\u2010resolution X\u2010ray crystal structure of the complex between inhibitor <jats:bold>5<\/jats:bold> and HIV\u20101 protease, which provides molecular insight into the unprecedented activity profiles observed.<\/jats:p>","DOI":"10.1002\/cmdc.201700824","type":"journal-article","created":{"date-parts":[[2018,2,13]],"date-time":"2018-02-13T11:50:31Z","timestamp":1518522631000},"page":"803-815","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Design of Highly Potent, Dual\u2010Acting and Central\u2010Nervous\u2010System\u2010Penetrating HIV\u20101 Protease Inhibitors with Excellent Potency against Multidrug\u2010Resistant HIV\u20101 Variants"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-1841","authenticated-orcid":false,"given":"Arun K.","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalapala Venkateswara","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanth R.","family":"Nyalapatla","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Kovela","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Brindisi","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Osswald","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavanam","family":"Sekhara\u2005Reddy","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnson","family":"Agniswamy","sequence":"additional","affiliation":[{"name":"Departments of Biology and Chemistry, Molecular Basis of Disease Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Biology and Chemistry, Molecular Basis of Disease Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Aoki","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases Kumamoto University School of Medicine  Kumamoto 860-8556 Japan"},{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute  Bethesda MD 20892 USA"},{"name":"Center for Clinical Sciences National Center for Global Heath and Medicine  Shinjuku Tokyo 162-8655 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin\u2010ichiro","family":"Hattori","sequence":"additional","affiliation":[{"name":"Center for Clinical Sciences National Center for Global Heath and Medicine  Shinjuku Tokyo 162-8655 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene T.","family":"Weber","sequence":"additional","affiliation":[{"name":"Departments of Biology and Chemistry, Molecular Basis of Disease Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases Kumamoto University School of Medicine  Kumamoto 860-8556 Japan"},{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute  Bethesda MD 20892 USA"},{"name":"Center for Clinical Sciences National Center for Global Heath and Medicine  Shinjuku Tokyo 162-8655 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,3,15]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1097\/QAI.0000000000001014","volume":"73","author":"Marcus J. 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