Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design

Thomas S. Peat, David I. Rhodes, Nick Vandegraaff, Giang Le, Jessica A. Smith, Lisa J. Clark, Eric D. Jones, Jonathan A.V. Coates, Neeranat Thienthong, Janet Newman, Olan Dolezal, Roger Mulder, John H. Ryan, G. Paul Savage, Craig L. Francis, John J. Deadman

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

Original languageEnglish
Article numbere40147
Number of pages11
JournalPLoS ONE
Volume7
Issue number7
DOIs
Publication statusPublished - 10 Jul 2012
Externally publishedYes

Cite this

Peat, Thomas S. ; Rhodes, David I. ; Vandegraaff, Nick ; Le, Giang ; Smith, Jessica A. ; Clark, Lisa J. ; Jones, Eric D. ; Coates, Jonathan A.V. ; Thienthong, Neeranat ; Newman, Janet ; Dolezal, Olan ; Mulder, Roger ; Ryan, John H. ; Savage, G. Paul ; Francis, Craig L. ; Deadman, John J. / Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. In: PLoS ONE. 2012 ; Vol. 7, No. 7.
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title = "Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design",
abstract = "A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.",
author = "Peat, {Thomas S.} and Rhodes, {David I.} and Nick Vandegraaff and Giang Le and Smith, {Jessica A.} and Clark, {Lisa J.} and Jones, {Eric D.} and Coates, {Jonathan A.V.} and Neeranat Thienthong and Janet Newman and Olan Dolezal and Roger Mulder and Ryan, {John H.} and Savage, {G. Paul} and Francis, {Craig L.} and Deadman, {John J.}",
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Peat, TS, Rhodes, DI, Vandegraaff, N, Le, G, Smith, JA, Clark, LJ, Jones, ED, Coates, JAV, Thienthong, N, Newman, J, Dolezal, O, Mulder, R, Ryan, JH, Savage, GP, Francis, CL & Deadman, JJ 2012, 'Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design' PLoS ONE, vol. 7, no. 7, e40147. https://doi.org/10.1371/journal.pone.0040147

Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. / Peat, Thomas S.; Rhodes, David I.; Vandegraaff, Nick; Le, Giang; Smith, Jessica A.; Clark, Lisa J.; Jones, Eric D.; Coates, Jonathan A.V.; Thienthong, Neeranat; Newman, Janet; Dolezal, Olan; Mulder, Roger; Ryan, John H.; Savage, G. Paul; Francis, Craig L.; Deadman, John J.

In: PLoS ONE, Vol. 7, No. 7, e40147, 10.07.2012.

Research output: Contribution to journalArticleResearchpeer-review

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