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Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV‐1 Integrase
Author(s) -
Northfield Susan E.,
Wielens Jerome,
Headey Stephen J.,
WilliamsNoonan Billy J.,
Mulcair Mark,
Scanlon Martin J.,
Parker Michael W.,
Thompson Philip E.,
Chalmers David K.
Publication year - 2018
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.201800129
Subject(s) - integrase , integrase inhibitor , loop (graph theory) , human immunodeficiency virus (hiv) , virology , computational biology , biology , genetics , antiretroviral therapy , combinatorics , viral load , mathematics
The p75 splice variant of lens epithelium‐derived growth factor (LEDGF) is a 75 kDa protein, which is recruited by the human immunodeficiency virus (HIV) to tether the pre‐integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Herein we present the X‐ray crystal structures, NMR studies, SPR analysis, and conformational studies of four cyclic peptides bound to the HIV‐1 integrase core domain. Although the X‐ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low millimolar range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low‐energy solution and bound conformations.