PMID: 9428710Jan 15, 1998Paper

Configurations of diastereomeric hydroxyethylene isosteres strongly affect biological activities of a series of specific inhibitors of human-immunodeficiency-virus proteinase

European Journal of Biochemistry
Jan KonvalinkaH G Kräusslich

Abstract

Human immunodeficiency virus (HIV) proteinase (PR) represents an important target for antiviral chemotherapy. We present an analysis of inhibitory activities of a series of pseudopeptide inhibitors of HIV-1 PR. All inhibitors were N-protected tetrapeptides with the scissile bond replaced by a nonhydrolysable hydroxyethylene or hydroxyethylamine isostere. To elucidate subtle structural requirements of the PR binding cleft, we synthesised inhibitors with four combinations of configurations at the asymmetric carbons of the isostere. Compounds were tested in vitro using purified recombinant enzyme and a chromogenic peptide substrate. The differences in inhibition constants between individual diastereoisomers reached three orders of magnitude. The most active hydroxyethylene-containing inhibitor possessed the 2R,4S,5S configuration at the isostere. Inhibitor activity was also tested in mammalian cell culture by analysing reduction of viral polyprotein processing and virus infectivity. The results obtained in tissue culture were generally in agreement with the in vitro data, giving a similar order of potency for the individual diastereoisomers. The most active compounds completely blocked production of infectious virus. A simulation ...Continue Reading

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Citations

Oct 25, 2000·Protein Science : a Publication of the Protein Society·K StrisovskyH G Kräusslich
Nov 25, 2004·European Journal of Biochemistry·Hana PetrokováJindrich Hasek
Aug 15, 2001·Antimicrobial Agents and Chemotherapy·K LindstenN P Dantuma
Sep 23, 2003·Protein Science : a Publication of the Protein Society·Marek IngrJan Konvalinka
Jun 19, 2008·Protein Science : a Publication of the Protein Society·Klára Grantz SaskováJan Konvalinka
Oct 26, 2005·Protein Expression and Purification·Péter BorossPéter Bagossi
May 26, 2004·Journal of Virological Methods·Péter BagossiJózsef Tözsér
Dec 3, 2009·Physical Chemistry Chemical Physics : PCCP·Jan HeydaJirí Vondrásek
Apr 7, 2011·The Journal of Physical Chemistry. B·Michal KolárPavel Hobza
Apr 18, 2003·Journal of Medicinal Chemistry·Tereza SkálováJan Konvalinka
Nov 9, 2004·Journal of Combinatorial Chemistry·Ramakrishna Sasubilli, William G Gutheil

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