PD 404,182 Is a Virocidal Small Molecule That Disrupts Hepatitis C Virus and Human Immunodeficiency Virus
- 1 February 2012
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 56 (2), 672-681
- https://doi.org/10.1128/aac.05722-11
Abstract
We describe a virucidal small molecule, PD 404,182, that is effective against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The median 50% inhibitory concentrations (IC 50 s) for the antiviral effect of PD 404,182 against HCV and HIV in cell culture are 11 and 1 μM, respectively. The antiviral activity of PD 404,182 is due to the physical disruption of virions that is accompanied to various degrees (depending on the virus and exposure temperature/time) by the release of viral nucleic acids into the surrounding medium. PD 404,182 does not directly lyse liposomal membranes even after extended exposure, and it shows no attenuation in antiviral activity when preincubated with liposomes of various lipid compositions, suggesting that the compound inactivates viruses through interaction with a nonlipid structural component of the virus. The virucidal activity of PD 404,182 appears to be virus specific, as little to no viral inactivation was detected with the enveloped Dengue and Sindbis viruses. PD 404,182 effectively inactivates a broad range of primary isolates of HIV-1 as well as HIV-2 and simian immunodeficiency virus (SIV), and it does not exhibit significant cytotoxicity with multiple human cell lines in vitro (50% cytotoxic concentration, >300 μM). The compound is fully active in cervical fluids, although it exhibits decreased potency in the presence of human serum, retains its full antiviral potency for 8 h when in contact with cells, and is effective against both cell-free and cell-associated HIV. These qualities make PD 404,182 an attractive candidate anti-HIV microbicide for the prevention of HIV transmission through sexual intercourse.This publication has 43 references indexed in Scilit:
- HIV/HCV Co-infection: Pathogenesis, Clinical Complications, Treatment, and New Therapeutic TechnologiesCurrent HIV/AIDS Reports, 2011
- A broad-spectrum antiviral targeting entry of enveloped virusesProceedings of the National Academy of Sciences of the United States of America, 2010
- CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clockProceedings of the National Academy of Sciences of the United States of America, 2009
- Composition and Three-Dimensional Architecture of the Dengue Virus Replication and Assembly SitesCell Host & Microbe, 2009
- Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseasesNature Medicine, 2008
- Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cellsHepatology, 2008
- Hepatitis C virus NS5A anchor peptide disrupts human immunodeficiency virusProceedings of the National Academy of Sciences of the United States of America, 2008
- A virocidal amphipathic α-helical peptide that inhibits hepatitis C virus infection in vitroProceedings of the National Academy of Sciences of the United States of America, 2008
- Claudin-1 is a hepatitis C virus co-receptor required for a late step in entryNature, 2007
- Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimerasProceedings of the National Academy of Sciences of the United States of America, 2006