Antiviral
Agents with Activity against Both HIV and Hepatitis C Virus By
Liz Highleyman Standard
therapy for chronic hepatitis C virus (HCV) infection
consists of pegylated interferon
plus ribavirin, but several novel agents under study directly target various
steps of the HCV lifecycle, an approach known as "STAT-C." Some
of these investigational agents work similarly to certain antiretroviral
drugs for HIV, suggesting it may be possible
to develop drugs that have activity against both HIV-HCV, a potential benefit
for HIV-HCV coinfected patients. EASL
Study
At
the recent 44th Annual Meeting of the European Association
for the Study of the Liver (EASL 2009) in Copenhagen, K. Klumpp and colleagues,
representing 3 pharmaceutical companies, described the identification of agents
with dual anti-HCV/anti-HIV activity.
HCV
polymerase and HIV reverse transcriptase (RT) have both been shown to accept modified
deoxynucleoside analogs as substrates when they copy their genetic material, the
researchers noted as background. Since these agents differ from natural nucleosides,
they can halt viral replication.
The investigators sought to identify nucleoside
analogs that inhibit both the RNA polymerase of HCV and the DNA polymerase of
HIV-RT, but do not interfere with natural human RNA and DNA polymerases, since
such interference could produce significant side effects.
Candidate nucleoside
analogs were tested for antiviral activity and cytotoxicity in various laboratory
models of infected cells (Con1 HCV replicon in Huh-7 cells, HXB2 HIV-1 in MT-4
cells, and Dengue virus replication in Huh-7 cells).
Nucleoside triphosphate
analogs were tested as inhibitors of viral and human RNA and DNA polymerases,
including HCV NS5B, Dengue NS5, West Nile virus NS5, HIV-1 reverse transcriptase,
cytomegalovirus (CMV) DNA polymerase, and human mitochondrial DNA polymerase-gamma.
Results
Screening of a series of nucleoside analogs known to inhibit HCV replication identified
novel cytidine analogs with potent anti-HIV-1 activity.
These agents exhibited anti-HIV potency superior to that of reference drugs:
Lamivudine (3TC; Epivir): 50%
inhibitory concentration (IC50) 2.5 mcM;
Emtricitabine (FTC; Emtriva):
IC50 0.43 mcM;
Zidovudine (AZT; Retrovir):
IC50 0.095 mcM.
The most potent compound, designated RO-0622, inhibited replication in the HCV
replicon model with an IC50 of 24 nM, and thus was about 50-fold more potent than
R1479 (the active version of R1626
in the body).
RO-0622 inhibited HIV-1 replication in MT-4 cells with an antiviral IC50 of 0.4
nM, and was therefore more than 6000-fold more potent than lamivudine.
RO-9187 also inhibited both HCV (IC50 171 nM) and HIV-1 replication (IC50 49 nM).
These compounds were not cytotoxic or cytostatic in HCV replicon cells and protected
HIV-infected cells from HIV-induced cell death.
The corresponding nucleoside triphosphates were competitive inhibitors of HCV
and HIV polymerases, but did not target human polymerases or other viral polymerases.
These
results led the researchers to conclude, "Novel nucleosides have been identified
that can inhibit both HCV and HIV replication with higher potency as compared
to reference compounds 3TC, FTC, AZT or R1479, while retaining selectivity against
human and other viral polymerases."
As
previously reported, another research team at EASL 2009 presented the latest
data on the cyclophilin inhibitor Debio 025, which
was previously shown to have activity against both HCV and HIV in preclinical
studies, although its anti-HIV effect was not strong in early clinical trials.
Roche,
Palo Alto, CA; Rigel Pharmaceuticals, South San Francisco, CA; Medivir AB, Huddinge,
Sweden.
Nelfinavir In
a study reported in the March 3, 2009 advance online edition of Journal of
Viral Hepatitis, Japanese researchers assessed whether the HIV protease inhibitor
nelfinavir (Viracept) might
also have activity against HCV. The
investigators evaluated the effects of nelfinavir on intracellular HCV replication
using an HCV replicon model expressing a neomycin-selectable chimeric firefly
luciferase reporter protein. Cytotoxicity and apoptosis induced by nelfinavir
were assessed and synergism between nelfinavir and interferon (IFN) was calculated
using CalcuSyn analysis. They
found that nelfinavir suppressed HCV replication in a dose-dependent manner at
low concentrations (IC50 9.88 mcM/L). Nelfinavir did not cause cytotoxicity or
apoptosis (programmed cell death) at concentrations that inhibited HCV replication.
When clinical concentrations of nelfinavir (5 mcM/L) were combined with interferon,
the 2 drugs exhibited synergistic inhibition of HCV replication in the replicon
model. Based
on these findings, the researchers concluded, "Our results suggest that the
direct effects of nelfinavir on the HCV subgenome and its synergism with interferon
could improve clinical responses to interferon therapy in HCV-HIV coinfected patients." First
Department of Internal Medicine, School of Medicine, University of the Ryukyus,
Okinawa, Japan. 6/2/09 References
K
Klumpp, G Su, J Deval, and others. 2'-Deoxy-Nucleoside Analogs as Potent Dual
Inhibitors of HCV and HIV Replication, with Selectivity against other Viral and
Human Polymerases. 44th Annual Meeting of the European Association for the Study
of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.
S Toma,
T Yamashiro, S Arakaki, and others. Inhibition of intracellular hepatitis C virus
replication by nelfinavir and synergistic effect with interferon-alpha. Journal
of Viral Hepatitis. March 3, 2009 [Epub ahead of print]
EASL
2009 MAIN PAGE
15th
Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage
by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
HIV and AIDS Treatment
News, Experimental News, FDA-approved News Highlights
of the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
- Coverage by HIV and Hepatitis.com, February 8 - 11, 2009, Montreal
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