1JLD

Potent hiv protease inhibitors containing a novel (hydroxyethyl)amide isostere

Summary for 1JLD

• Entry DOI: 10.2210/pdb1jld/pdb
• Related PRD ID: PRD_000341
• Descriptor: Pol polyprotein, (2S)-2-tert-butyl-N~4~-(1-ethylpropyl)-N~1~-[(2R,3S)-2-hydroxy-4-phenyl-3-{[N-(quinolin-2-ylcarbonyl)-L-threonyl]amino}butyl]butanediamide (3 entities in total)
• Functional Keywords: polyprotein, hiv-2 protease, hydrolase-hydrolase inhibitor complex, aids, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 2
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): Q7SKJ2
• Total number of polymer chains: 2
• Total formula weight: 22118.50

Authors

Tong, L. (deposition date: 1997-05-31, release date: 1997-12-03, Last modification date: 2024-02-07)

Primary citation

Beaulieu, P.L.,Wernic, D.,Abraham, A.,Anderson, P.C.,Bogri, T.,Bousquet, Y.,Croteau, G.,Guse, I.,Lamarre, D.,Liard, F.,Paris, W.,Thibeault, D.,Pav, S.,Tong, L.
Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere.
J.Med.Chem., 40:2164-2176, 1997

PubMed Abstract: A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.

PubMed: 9216835
DOI: 10.1021/jm9606608

Experimental method

X-RAY DIFFRACTION (2.5 Å)