Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule: The HIV-1 CD4:gp120 paradigm

Mattan Hurevich*, Avi Swed, Salim Joubran, Shira Cohen, Noam S. Freeman, Elena Britan-Rosich, Laurence Briant-Longuet, Martine Bardy, Christian Devaux, Moshe Kotler, Amnon Hoffman, Chaim Gilon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Rational conversion of noncontinuous active regions of proteins into a small orally bioavailable molecule is crucial for the discovery of new drugs based on inhibition of protein-protein interactions. We developed a method that utilizes backbone cyclization as an intermediate step for conversion of the CD4 noncontinuous active region into small macrocyclic molecules. We demonstrate that this method is feasible by preparing small inhibitor for human immunodeficiency virus infection. The lead compound, CG-1, proved orally available in the rat model.

Original languageAmerican English
Pages (from-to)5754-5761
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number15
DOIs
StatePublished - 1 Aug 2010

Keywords

  • Backbone cyclization
  • Drug design
  • HIV-1
  • Macrocycles
  • Proteomics

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