当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > 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.

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.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Howard OM,Oppenheim JJ,Hollingshead MG,Covey JM,Bigelow J,McCormack JJ,Buckheit RW Jr,Clanton DJ,Turpin JA,Rice WG

doi

10.1021/jm9801253

subject

Has Abstract

pub_date

1998-06-18 00:00:00

pages

2184-93

issue

13

eissn

0022-2623

issn

1520-4804

pii

jm9801253

journal_volume

41

pub_type

杂志文章

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