Evaluation of PD 404,182 as an anti-HIV and anti-herpes simplex virus microbicide.
PD 404,182 (PD) is a synthetic compound that was found to compromise HIV integrity via interaction with a nonenvelope protein viral structural component (A. M. Chamoun et al., Antimicrob. Agents Chemother. 56:672-681, 2012). The present study evaluates the potential of PD as an anti-HIV microbicide and establishes PD's virucidal activity toward another pathogen, herpes simplex virus (HSV). We show that the anti-HIV-1 50% inhibitory concentration (IC50) of PD, when diluted in seminal plasma, is ∼1 μM, similar to the IC50 determined in cell culture growth medium, and that PD retains full anti-HIV-1 activity after incubation in cervical fluid at 37°C for at least 24 h. In addition, PD is nontoxic toward vaginal commensal Lactobacillus species (50% cytotoxic concentration [CC50], >300 μM), freshly activated human peripheral blood mononuclear cells (CC50, ∼200 μM), and primary CD4(+) T cells, macrophages, and dendritic cells (CC50, >300 μM). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans.
Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA.
Ana M
AM
Chamoun-Emanuelli
Michael
M
Bobardt
Bernard
B
Moncla
Marie K
MK
Mankowski
Roger G
RG
Ptak
Philippe
P
Gallay
Zhilei
Z
Chen
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D004355:Drug Stability; D045604:Extracellular Fluid / Q000737:chemistry; D005260:Female; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D007097:Imines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D061251:Primary Cell Culture; D012661:Semen / Q000737:chemistry; D013696:Temperature; D013843:Thiazines / Q000494:pharmacology*; D014709:Vero Cells
C586214:6H-6-imino-(2,3,4,5-tetrahydropyrimido)(1,2-c)-(1,3)benzothiazine; D000998:Antiviral Agents; D007097:Imines; D013843:Thiazines