Article (Scientific journals)
Agonist-induced internalization of CC chemokine receptor 5 as a mechanism to inhibit HIV replication.
Ferain, Thierry; Hoveyda, Hamid; Ooms, Frédéric et al.
2011In Journal of Pharmacology and Experimental Therapeutics, 337 (3), p. 655 - 662
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Keywords :
2-(4-cyanophenyl)-N-(1-(1-(N,1-diphenylmethylsulfonamido)propan-2-yl)piperidin-4-yl)acetamide; Anti-HIV Agents; Benzeneacetamides; CCR5 Receptor Antagonists; Chemokine CCL5; Chemokines; Cyclohexanes; Receptors, CCR5; Receptors, CXCR4; Sulfonamides; Triazoles; Maraviroc; Animals; Anti-HIV Agents/pharmacology; Benzeneacetamides/pharmacology; Cell Line; Chemokine CCL5/metabolism; Chemokine CCL5/pharmacology; Chemokines/metabolism; Chemotaxis/drug effects; Chemotaxis/genetics; Cricetinae; Cyclohexanes/pharmacology; DNA Replication/drug effects; Drug Resistance, Multiple, Viral; HEK293 Cells; HIV Infections/drug therapy; HIV Infections/genetics; HIV Infections/virology; HIV-1/drug effects; HIV-1/genetics; HIV-1/metabolism; Humans; Leukocytes, Mononuclear/drug effects; Leukocytes, Mononuclear/virology; Macrophages/drug effects; Macrophages/virology; Protein Binding; Receptors, CCR5/agonists; Receptors, CCR5/genetics; Receptors, CCR5/metabolism; Receptors, CXCR4/antagonists & inhibitors; Receptors, CXCR4/genetics; Receptors, CXCR4/metabolism; Sulfonamides/pharmacology; Triazoles/pharmacology; Virus Replication/drug effects; Molecular Medicine; Pharmacology
Abstract :
[en] The chemokine G protein-coupled receptor CC chemokine receptor 5 (CCR5) is used as an entry gate by CCR5-tropic and dual- or CCR5/CXC chemokine receptor 4-tropic strains of HIV to enter the human host cells. Thus, CCR5 antagonists (i.e., maraviroc) have been proven to be clinically effective by preventing the interaction between viral glycoprotein 120 and CCR5 and thus impeding viral entry into host cells. However, the emergence of HIV strains resistant to CCR5 antagonists has been reported in vitro and in vivo, where the virus has adapted to enter the cells via antagonist-bound CCR5. An alternative strategy that should obviate this mode of viral resistance would entail the ablation of the CCR5 portal for HIV entry from the cell surface through agonist-induced receptor internalization. Although this protective effect has been demonstrated clearly with natural CCR5 ligands, the chemoattractant properties of these chemokines have precluded them from further consideration in terms of drug development. Thus, we sought to explore the possibility of developing novel small molecules and selective CCR5 agonists devoid of eliciting chemotaxis. Indeed, the CCR5 agonists described herein were found to induce profound down-modulation of CCR5 (and not CXC chemokine receptor 4) from the cell surface and its sustained sequestration in the intracellular compartment without inducing chemotaxis in vitro. The bioactivity profile of these novel CCR5 agonists is exemplified by the compound (R)-2-(4-cyanophenyl)-N-(1-(1-(N,1-diphenylmethylsulfonamido)propan-2-yl)piperidin-4-yl)acetamide (ESN-196) that potently inhibits HIV-1 infection in human peripheral blood mononuclear cells and macrophages in vitro with potencies comparable to that of maraviroc and moreover demonstrates full activity against a maraviroc-resistant HIV-1 RU570 strain.
Disciplines :
Chemistry
Author, co-author :
Ferain, Thierry;  Euroscreen S.A., Rue Adrienne Bolland, 47, B-6041 Gosselies, Belgium. tferain@euroscreen.com
Hoveyda, Hamid;  Euroscreen S.A., B-6041 Gosselies, Belgium
Ooms, Frédéric  ;  Université de Liège - ULiège > HEC Liège Research > HEC Liège Research: Strategy & Performance for the Society ; Sopartec, Louvain-la-Neuve, Belgium
Schols, Dominique;  Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
Bernard, Jérôme;  Euroscreen S.A., B-6041 Gosselies, Belgium
Fraser, Graeme;  Euroscreen S.A., B-6041 Gosselies, Belgium
Language :
English
Title :
Agonist-induced internalization of CC chemokine receptor 5 as a mechanism to inhibit HIV replication.
Publication date :
June 2011
Journal title :
Journal of Pharmacology and Experimental Therapeutics
ISSN :
0022-3565
eISSN :
1521-0103
Publisher :
American Society for Pharmacology & Experimental Therapeutics (ASPET), United States
Volume :
337
Issue :
3
Pages :
655 - 662
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 02 July 2024

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