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PD 404,182 is a virucidal small molecule that disrupts hepatitis C virus and human immunodeficiency virus

1. Ana Maria Chamouna,
2. Karuppiah Chockalingama,
3. Michael Bobardtc,
4. Rudo Simeona,
5. Jinhong Changd,
6. Philippe Gallayc,1 and
7. Zhilei Chena,b,1

+ Author Affiliations

1. ^aArtie McFerrin Department of Chemical Engineering, Texas A&M University, 3122 TAMU, College Station, TX 77843
2. ^bDepartment of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College Station, TX 77843
3. ^cDepartment of Immunology and Microbial Sciences, IMM-9, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
4. ^dDrexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA 18902

ABSTRACT

We describe a virucidal small molecule, PD 404,182, effective against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The median IC₅₀ values for the antiviral effect of PD 404,182 against HCV and HIV in cell culture are 11 μM and 1 μM, respectively. The antiviral activity of PD 404,182 is due to physical disruption of virions that is accompanied to varying degrees (depending on the virus and exposure temperature/time) by release of viral nucleic acids into the surrounding medium. PD 404,182 does not directly lyse liposomal membranes even after extended exposure and shows no attenuation in antiviral activity when pre-incubated with liposomes of various lipid compositions, suggesting that the compound inactivates viruses through interaction with a non-lipid 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 does not exhibit significant cytotoxicity with multiple human cell lines in vitro (CC₅₀ > 300 μM). The compound is fully active in cervical fluids although exhibiting decreased potency in the presence of human serum, retains its full antiviral potency for over 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 microbicide for the prevention of HIV transmission through sexual intercourse.