Premium
Targeting the Open‐Flap Conformation of HIV‐1 Protease with Pyrrolidine‐Based Inhibitors
Author(s) -
Böttcher Jark,
Blum Andreas,
Dörr Stefanie,
Heine Andreas,
Diederich Wibke E.,
Klebe Gerhard
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800113
Subject(s) - pyrrolidine , human immunodeficiency virus (hiv) , protease , hiv 1 protease , chemistry , stereochemistry , combinatorial chemistry , pharmacology , virology , biochemistry , medicine , enzyme
HIV protease is a well‐established drug target in antiviral chemotherapy. Immense research efforts have been made to discover effective inhibitors, thus making the enzyme one of the most studied and best characterized proteins. Although the protease exhibits high flexibility, all approved drugs target virtually the same protein conformation. The development of viral cross‐resistance demands the generation of inhibitors with novel scaffolds and deviating modes of binding. Herein we report the design and the short, high‐yielding stereoselective synthesis of a series of chiral, symmetric pyrrolidine‐based inhibitors targeting the open‐flap conformation of the protease. The obtained co‐crystal structure with one derivative provides a valuable starting point for further inhibitor design.