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Title: Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants

Journal Article · · ChemMedChem
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [4];  [2];  [3]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. School of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Heath and Medicine, Tokyo (Japan)
  4. National Center for Global Heath and Medicine, Tokyo (Japan)
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Herein we report the design, synthesis, X–ray structural, and biological studies of an exceptionally potent HIV–1 protease inhibitor, compound 5 ((3S,7aS,8S)–hexahydro–4H–3,5–methanofuro[2,3–b]pyran–8–yl ((2S,3R)–4–((2–(cyclopropylamino)–N–isobutylbenzo[d]thiazole)–6–sulfonamido)–1–(3,5–difluorophenyl)–3–hydroxybutan–2–yl)carbamate). Using structure–based design, we incorporated an unprecedented 6–5–5–ring–fused crown–like tetrahydropyranofuran as the P2–ligand, a cyclopropylaminobenzothiazole as the P2'–igand, and a 3,5–difluorophenylmethyl group as the P1–ligand. The resulting inhibitor 5 exhibited exceptional HIV–1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug–resistant HIV–1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug…resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. Here, we determined a high–resolution X–ray crystal structure of the complex between inhibitor 5 and HIV–1 protease, which provides molecular insight into the unprecedented activity profiles observed.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of General Medical Sciences; National Inst. of Health
Grant/Contract Number:
GM53386; GM62920
OSTI ID:
1435833
Journal Information:
ChemMedChem, Vol. 13, Issue 8; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 33 works
Citation information provided by
Web of Science

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Cited By (5)

Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors journal June 2018
Potent HIV‐1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein‐Ligand X‐ray Structural Studies journal October 2019
Asymmetric Diels–Alder reaction of 3-(acyloxy)acryloyl oxazolidinones: optically active synthesis of a high-affinity ligand for potent HIV-1 protease inhibitors journal January 2019
Novel Protease Inhibitors Containing C-5-Modified bis -Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance journal May 2019
Classification of HIV-1 Protease Inhibitors by Machine Learning Methods journal November 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
antiviral agents
brain penetration
drug resistance
HIV-1 protease
structure-based design