Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

2005 ◽  
Vol 7 (5) ◽  
pp. 493-500 ◽  
Author(s):  
Alan Lau ◽  
Karra M. Swinbank ◽  
Parvin S. Ahmed ◽  
Debra L. Taylor ◽  
Stephen P. Jackson ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Atm Kinase ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function

1998 ◽  
Vol 64 (1) ◽  
pp. 6-13 ◽  
Author(s):  
O. M. Z. Howard ◽  
Thomas Korte ◽  
Nadya I. Tarasova ◽  
Michael Grimm ◽  
Jim A. Turpin ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

Identification of a Novel Small Molecule Inhibitor that Targets HIV-1 Envelope Maturation

2007 ◽  
Vol 74 (3) ◽  
pp. A27-A27
Author(s):  
J JIMENEZ ◽  
J CAO ◽  
L JACKSON ◽  
Q PENG ◽  
H WU ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

1997 ◽  
Vol 186 (8) ◽  
pp. 1395-1400 ◽  
Author(s):  
Benjamin J. Doranz ◽  
Kathie Grovit-Ferbas ◽  
Matthew P. Sharron ◽  
Si-Hua Mao ◽  
Matthew Bidwell Goetz ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Viral Entry ◽  
Small Molecule Inhibitor ◽  
Chemokine Receptor Cxcr4 ◽  
Mechanism Of Inhibition ◽  
Molecule Inhibitor ◽  
Immunodeficiency Virus ◽  
Hiv 1

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell– tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1α–mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

A small-molecule inhibitor of HIV-1 Rev function detected by a diversity screen based on RRE-Rev interference

2018 ◽  
Vol 156 ◽  
pp. 68-77 ◽  
Author(s):  
Silvia Prado ◽  
Manuela Beltrán ◽  
Ángela Moreno ◽  
Luis M. Bedoya ◽  
José Alcamí ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor

1998 ◽  
Vol 4 (1) ◽  
pp. 72-77 ◽  
Author(s):  
George A. Donzella ◽  
Dominique Schols ◽  
Steven W. Lin ◽  
José A. Esté ◽  
Kirsten A. Nagashima ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5

2000 ◽  
Vol 97 (10) ◽  
pp. 5639-5644 ◽  
Author(s):  
T. Dragic ◽  
A. Trkola ◽  
D. A. D. Thompson ◽  
E. G. Cormier ◽  
F. A. Kajumo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Pocket ◽  
Small Molecule Inhibitor ◽  
Transmembrane Helices ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry

2015 ◽  
Vol 89 (17) ◽  
pp. 9068-9079 ◽  
Author(s):  
Jing Zhou ◽  
Amanda J. Price ◽  
Upul D. Halambage ◽  
Leo C. James ◽  
Christopher Aiken
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Mutant Virus ◽  
Host Factors ◽  
Nuclear Entry ◽  
Molecule Inhibitor ◽  
Clinical Resistance ◽  
Hiv 1

ABSTRACTDuring HIV-1 infection of cells, the viral capsid plays critical roles in reverse transcription and nuclear entry of the virus. The capsid-targeting small molecule PF74 inhibits HIV-1 at early stages of infection. HIV-1 resistance to PF74 is complex, requiring multiple amino acid substitutions in the viral CA protein. Here we report the identification and analysis of a novel PF74-resistant mutant encoding amino acid changes in both domains of CA, three of which are near the pocket where PF74 binds. Interestingly, the mutant virus retained partial PF74 binding, and its replication was stimulated by the compound. The mutant capsid structure was not significantly perturbed by binding of PF74; rather, the mutations inhibited capsid interactions with CPSF6 and Nup153 and altered HIV-1 dependence on these host factors and on TNPO3. Moreover, the replication of the mutant virus was markedly impaired in activated primary CD4+T cells and macrophages. Our results suggest that HIV-1 escapes a capsid-targeting small molecule inhibitor by altering the virus's dependence on host factors normally required for entry into the nucleus. They further imply that clinical resistance to inhibitors targeting the PF74 binding pocket is likely to be strongly limited by functional constraints on HIV-1 evolution.IMPORTANCEThe HIV-1 capsid plays critical roles in early steps of infection and is an attractive target for therapy. Here we show that selection for resistance to a capsid-targeting small molecule inhibitor can result in viral dependence on the compound. The mutant virus was debilitated in primary T cells and macrophages—cellular targets of infectionin vivo. The mutations also altered the virus's dependence on cellular factors that are normally required for HIV-1 entry into the nucleus. This work provides new information regarding mechanisms of HIV-1 resistance that should be useful in efforts to develop clinically useful drugs targeting the HIV-1 capsid.

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