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Chemicals Targeting an HIV‐1 Nef/Host Cell Kinase Complex as Novel Anti‐Retroviral Compounds
Author(s) -
Day Billy,
Adepegba Damilola
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb428
Subject(s) - kinase , viral replication , microbiology and biotechnology , protein–protein interaction , chemistry , scaffold protein , cytotoxicity , human immunodeficiency virus (hiv) , computational biology , small molecule , biology , virology , signal transduction , virus , biochemistry , in vitro
The AIDS epidemic has resulted in the development of many anti‐retroviral drugs to manage this deadly disease. Nef has been identified to be an essential protein in the progression of AIDS. Nef forms a complex with its host cell binding partner, the Src family kinase Hck. Nef activates Hck through a mechanism that involves displacement of the SH3 domain from a negative regulatory interaction with the catalytic domain. Nef, is known to influence signaling molecules, such as protein kinases. These characteristics that Nef acquire enhance the viral replication, as well as survival of infected cells. A high‐throughput screening assay identified two classes of inhibitors of this protein‐protein interaction. One class of inhibitors of HIV activity and Nef:Hck interaction was diphenylfuropyrimidines, the other 2‐arylsulfonamido‐3‐arylaminequinoxalines. Remarkably, these agents block Nef‐dependent HIV replication and show no cytotoxicity. This study shows a new and valid approach toward the development of anti‐HIV agents through synthesis, purification, and characterization of the different derivates of the scaffold identified to inhibit the protein‐protein interaction. These compound(s) could provide the structural scaffold for a new class(es) of anti‐HIV chemotherapeutics. Supported by NIH T34GM008411