2WL0

HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimic with Improved Cell-Based Antiviral Activity

Summary for 2WL0

• Entry DOI: 10.2210/pdb2wl0/pdb
• Related: 1A9M 1AJV 1AJX 1AXA 1BQM 1BQN 1D4H 1D4I 1D4J 1DLO 1DW6 1EBK 1EBW 1EBY 1EBZ 1EC0 1EC1 1EC2 1EC3 1EET 1HAR 1HBV 1HEF 1HEG 1HIH 1HMV 1HNI 1HNV 1HOS 1HPS 1HPZ 1HQE 1HQU 1HRH 1HTE 1HTF 1HTG 1HVK 1HVP 1HVU 1HYS 1IKV 1IKW 1IKX 1IKY 1J5O 1MER 1MES 1MET 1MEU 1N5Y 1N6Q 1NPA 1NPV 1NPW 1QE1 1QMC 1R0A 1RDH 1RTD 1RVL 1RVM 1RVN 1RVO 1RVP 1RVQ 1RVR 1S6P 1S6Q 1S9E 1S9G 1SBG 1SUQ 1SV5 1T03 1T05 1T7K 1TV6 1TVR 1UWB 1W5V 1W5W 1W5X 1W5Y 1YT9 2B5J 2B6A 2BAN 2BBB 2BE2 2HMI 2UXZ 2UY0 2VG5 2VG6 2VG7 2WKZ 3HVT 3TLH
• Descriptor: PROTEASE, METHYL [(1S)-1-({2-[(3S)-3-BENZYL-3-HYDROXY-4-{[(1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL]AMINO}-4-OXOBUTYL]-2-(4-PYRIDIN-2-YLBENZYL)HYDRAZINO}CARBONYL)-2,2-DIMETHYLPROPYL]CARBAMATE (3 entities in total)
• Functional Keywords: transition-state mimic, inhibitor, hydrolase
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (Z2/CDC-Z34 ISOLATE) (HIV-1)
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366
• Total number of polymer chains: 2
• Total formula weight: 22245.15

Authors

Mahalingam, A.K.,Axelsson, L.,Ekegren, J.K.,Wannberg, J.,Kihlstrom, J.,Wallberg, H.,Samuelsson, B.,Larhed, M.,Hallberg, A.,Unge, T. (deposition date: 2009-06-19, release date: 2009-12-15, Last modification date: 2023-12-13)

Primary citation

Mahalingam, A.K.,Axelsson, L.,Ekegren, J.K.,Wannberg, J.,Kihlstr, J.,Unge, T.,Wallberg, H.,Samuelsson, B.,Larhed, M.,Hallberg, A.
HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells.
J.Med.Chem., 53:607-, 2010

PubMed Abstract: By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.

PubMed: 19961222
DOI: 10.1021/JM901165G

Experimental method

X-RAY DIFFRACTION (1.9 Å)