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BIOLOGICAL SCIENCES / BIOPHYSICS
Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium
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*Department of Organic Chemistry, Department of Biological Chemistry, ¶Protein Purification Unit, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel; Department of Pathology, Hebrew University–Hadassah Medical School, Jerusalem 91120, Israel; Department of Cell and Developmental Biology, The Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and ||Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom
Edited by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, and approved March 27, 2007 (received for review January 30, 2007)
Proteins are involved in various equilibria that play a major role in their activity or regulation. The design of molecules that shift such equilibria is of great therapeutic potential. This fact was demonstrated in the cases of allosteric inhibitors, which shift the equilibrium between active and inactive (R and T) states, and chemical chaperones, which shift folding equilibrium of proteins. Here, we expand these concepts and propose the shifting of oligomerization equilibrium of proteins as a general methodology for drug design. We present a strategy for inhibiting proteins by "shiftides": ligands that specifically bind to an inactive oligomeric state of a disease-related protein and modulate its activity by shifting the oligomerization equilibrium of the protein toward it. We demonstrate the feasibility of our approach for the inhibition of the HIV-1 integrase (IN) protein by using peptides derived from its cellular-binding protein, LEDGF/p75, which specifically inhibit IN activity by a noncompetitive mechanism. The peptides inhibit the DNA-binding of IN by shifting the IN oligomerization equilibrium from the active dimer toward the inactive tetramer, which is unable to catalyze the first integration step of 3' end processing. The LEDGF/p75-derived peptides inhibit the enzymatic activity of IN in vitro and consequently block HIV-1 replication in cells because of the lack of integration. These peptides are promising anti-HIV lead compounds that modulate oligomerization of IN via a previously uncharacterized mechanism, which bears advantages over the conventional interface dimerization inhibitors.
allostery | protein equilibrium | shiftides | peptides | drug design
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
**To whom correspondence should be addressed. E-mail: assaf{at}chem.ch.huji.ac.il
© 2007 by The National Academy of Sciences of the USA
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