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

doi: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

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 journal › Article › Research › peer-review

54 Citations (Scopus)

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 language	English
Article number	e40147
Number of pages	11
Journal	PLoS ONE
Volume	7
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0040147
Publication status	Published - 10 Jul 2012
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1371/journal.pone.0040147

184453464Final published version, 683 KB

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Peat, T. S., Rhodes, D. I., Vandegraaff, N., Le, G., Smith, J. A., Clark, L. J., Jones, E. D., Coates, J. A. V., Thienthong, N., Newman, J., Dolezal, O., Mulder, R., Ryan, J. H., Savage, G. P., Francis, C. L., & Deadman, J. J. (2012). Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. PLoS ONE, 7(7), Article e40147. https://doi.org/10.1371/journal.pone.0040147

@article{be4e7c45fa9b4ba69d3d381eb2174514,

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.\}",

year = "2012",

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doi = "10.1371/journal.pone.0040147",

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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

TY - JOUR

T1 - Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design

AU - Peat, Thomas S.

AU - Rhodes, David I.

AU - Vandegraaff, Nick

AU - Le, Giang

AU - Smith, Jessica A.

AU - Clark, Lisa J.

AU - Jones, Eric D.

AU - Coates, Jonathan A.V.

AU - Thienthong, Neeranat

AU - Newman, Janet

AU - Dolezal, Olan

AU - Mulder, Roger

AU - Ryan, John H.

AU - Savage, G. Paul

AU - Francis, Craig L.

AU - Deadman, John J.

PY - 2012/7/10

Y1 - 2012/7/10

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0040147

M3 - Article

C2 - 22808106

AN - SCOPUS:84863689623

SN - 1932-6203

VL - 7

JO - PLoS ONE

JF - PLoS ONE

IS - 7

M1 - e40147

ER -

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

Abstract

UN SDGs

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Correction: Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design (PLoS ONE)

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

Abstract

UN SDGs

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Research output

Correction: Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design (PLoS ONE)

Equipment

Australian Synchrotron

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