HOPKINS TA, HUANG A, OIEN NL, VAILLANCOURT VA, WATHEN MW; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. F-1668.
Pharmacia Corporation, Kalamazoo, MI
BACKGROUND: Broad screening of the Pharmacia compound collection has led to the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQ) class of antivirals with specificity towards herpesviruses. These novel non-nucleoside compounds demonstrate potent inhibition of human cytomegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), and varicella zoster virus (VZV) polymerases, but do not inhibit human alpha, delta or gamma polymerases. METHODS: To determine if the activity of 4-HQ herpesvirus polymerase inhibitors extend to the gamma herpesviruses such as Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8), we cloned their polymerases and requisite accessory binding proteins. Inhibition by the 4-HQs was evaluated in polymerase assays using in vitro transcribed/translated polymerases and accessory binding proteins. RESULTS: The 4-HQs potently inhibited the EBV and HHV-8 polymerases with IC[50] values typically ranging from 1-10 micro-M. These results were similar to the activity of 4-HQs against the HCMV and HSV-1 polymerases under equivalent assay conditions. In addition, these compounds potently inhibited EBV and HHV-8 replication in antiviral cell culture based assays. PNU-183792, one of our leading compounds, was 25x more potent than acyclovir at inhibiting EBV DNA replication. CONCLUSIONS: The 4-HQs represent a novel class of non-nucleoside antivirals with the potential for treating many of the diseases caused by herpesviruses including EBV and HHV-8.
Publication Types:
Keywords:
- Acyclovir
- Antiviral Agents
- Cytomegalovirus
- Ganciclovir
- Herpesviridae
- Herpesviridae Infections
- Herpesvirus 1, Human
- Herpesvirus 3, Human
- Herpesvirus 4, Human
- Herpesvirus 8, Human
- Humans
- Hydroxyquinolines
- In Vitro
- Nucleosides
- PNU183792
- Quinolines
- Sarcoma, Kaposi
- methods
Other ID:
UI: 102269970
From Meeting Abstracts