Inhibition of in vitro and in vivo HIV replication by a distamycin analogue that interferes with chemokine receptor function: a candidate for chemotherapeutic and microbicidal application.
Select chemokine receptors act as coreceptors for HIV-1 entry into human cells and represent targets for antiviral therapy. In this report we describe a distamycin analogue, 2,2'-[4, 4'-[[aminocarbonyl]amino]bis[N,4'-di[pryrrole-2-carboxamide- 1, 1'-dimethyl]]-6,8-naphthalenedisulfonic acid]hexasodium salt (NSC 651016), that selectively inhibited chemokine binding to CCR5, CCR3, CCR1, and CXCR4, but not to CXCR2 or CCR2b, and blocked chemokine-induced calcium flux. Inhibition was not due to nonspecific charge interactions at the cell surface, but was based on a specific competition for the ligand receptor interaction sites since the inhibitory effect was specific for some but not all chemoattractant receptors. NSC 651016 inhibited in vitro replication of a wide range of HIV-1 isolates, as well as HIV-2 and SIV, and exhibited in vivo anti-HIV-1 activity in a murine model. In contrast, a distamycin analogue with similar structure and charge and the monomeric form of NSC 651016 demonstrated no inhibitory effects. These data demonstrate that molecules which interfere with HIV-1 entry into cells by targeting specific chemokine coreceptors can provide a viable approach to anti-HIV-1 therapy. NSC 651016 represents an attractive candidate for the chemotherapeutic treatment of HIV-1 infection and as a microbicide to prevent the sexual transmisssion of HIV-1. Moreover, NSC 651016 can serve as a template for medicinal chemical modifications leading to more effective antivirals.
Howard
O M
OM
Anti-AIDS Virus Drug Screening Laboratory, SAIC Frederick, Maryland 21702, USA.
Oppenheim
J J
JJ
Hollingshead
M G
MG
Covey
J M
JM
Bigelow
J
J
McCormack
J J
JJ
Buckheit
R W
RW
Clanton
D J
DJ
Turpin
J A
JA
Rice
W G
WG
D000279:Administration, Cutaneous; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008024:Ligands; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009282:Naphthalenesulfonates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000276:immunology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000302:isolation & purification; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D008024:Ligands; C112855:NSC 651016; D009282:Naphthalenesulfonates; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D018894:Reverse Transcriptase Inhibitors; D002118:Calcium