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AIDS Therapies New NNRTI Is Potential Vaginal Barrier to HIV
08/04/97
Disease Weekly Plus
Copyright 1997 Information Access Company. All rights reserved.
A new member of a subfamily of non-nucleoside reverse transcriptase
inhibitors (NNRTIs) renders HIV-1 non-infectious.
This ability suggests that the drug, UC781, could be used in topical vaginal
microbicides to prevent the sexual transmission of HIV.
"Preincubation of uninfected MT2 cells with UC781 rendered these cells
refractory to subsequent HIV infection in the absence of extracellular drug, an
effect that persisted for several days following removal of exogenous drug,"
reported Gadi Borkow and colleagues of McGill University AIDS Center,
Montreal, Quebec, Canada. "These unique properties of UC781 indicate that
this nonnucleoside inhibitor [NNI] may have considerable promise for use in
retrovirucidal formulations to minimize the spread of HIV from infected to
non-infected individuals."
Borkow et al. announced their findings in the Journal of Virology ("Chemical
Barriers to Human Immunodeficiency Virus Type 1 (HIV-1) Infection:
Retrovirucidal Activity of UC781, A Thiocarboxanilide Nonnucleoside Inhibitor
of HIV-1 Reverse Transcriptase," J Virol, 1997;71(4):3023-30.
UC781 is
N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothio
amide. It is the latest in the series of oxathiin carboxanilide (OC) derivatives
developed by Uniroyal Chemical Co.
National Cancer Institute researchers discovered oxathiin carboxanilide (OC,
dubbed UC84 by its manufacturer) as a result of the federal institute's
massive anti-HIV drug screening program. OC (itself an analog of the
commercial fungicide Vitavax) inhibits HIV reproduction and protects cells
from HIV cytopathicity. Although its mechanism of action was difficult to
determine at first, OC and its derivatives now are considered members of the
non-nucleoside reverse transcriptase inhibitors (NNRTIs).
During their evaluation of UC781, Borkow et al. found that the drug not only
bound with extreme affinity to HIV-1 reverse transcriptase (RT), but also
eliminated viral infectivity in a dose-dependent fashion.
"Neither nevirapine nor certain other carboxanilide nonnucleoside inhibitors
[UC38 or UC84] were effective in this manner," they noted.
When the researchers treated chronically HIV infected H9 cells with UC781,
virus production was not diminished. The ability of the progeny virus to infect
new cells was markedly reduced, though - even after exogenous drug was
removed from the culture.
Borkow et al. then exposed cultures of peripheral blood mononuclear cells
(PBMCs) from patients with HIV infection to UC781. These cells, infected
with various wild-type HIV-1 strains, also produced non-infectious virus. Again
the effect persisted after the drug was removed from the culture media.
Even more impressively, the researchers found that exposure of uninfected,
HIV susceptible cells to UC781 rendered them impervious to HIV-1 infection.
"The window of efficacy of UC781 in our experimental conditions is a complex
function of the resident intracellular lifetime of UC781 and the amount and
stability of HIV in the extracellular culture and other intracellular subviral
ribonucleoprotein complex," Borkow et al. wrote. "The intracellular half-life of
UC781 as a chemical barrier to HIV-1 infection in MT2 cells in vitro is about
5.5 days in cells pretreated with 10 (micro)M UC781."
The authors suggested several ways UC781 could be of benefit in a
microbicidal formulation:
* It inactivates free virus.
* Infected cells exposed to the drug produce virus with attenuated infectivity.
* UC781 is effective against wild-type patient isolates of HIV-1.
* The drug is taken up by uninfected cells where it exerts a protective effect
for an extended period.
"Thus, UC781 may serve as an effective retrovirucide or vaginal microbicide
to minimize the sexual transmission of HIV-1 from infected to non-infected
individuals," Borkow et al. concluded. "An important advantage of the use of
NNI in this manner is that viral resistance would not develop since the drug
would be used primarily by non-infected individuals."
The authors suggested that UC781 would likely be combined with other
topical microbicides, such as modified (beta)-lactoglobulin or nonoxynol-9, to
maximize the protective activity of the product. But they warn that thorough
testing will be required.
"Repeated use of UC781 as a microbicidal agent would result in prolonged
chronic exposure of sexually active women to the compound," they warned.
"The exposure of uninfected healthy individuals to UC781 could be justified
only if this compound lacks any toxicity and side effects at concentrations
sufficient to prevent HIV-1 transmission in vivo."
Borkow et al. also suggested that UC781 remains a potential systemic
anti-HIV-1 drug for people already infected. The OC derivatives have excellent
pharmacokinetic properties, and a recent study showed that UC781 is active
against many HIV-1 strains resistant to other NNRTIs (Balzarini et al.,
Antimic Ag Chem, 1996;40:1454-66).
Moreover, Borkow et al. reported that their own unpublished data show "that
the time required for the development of HIV-1 resistance to UC781 is
significantly prolonged relative to that for most other NNI."
The authors currently are working to develop UC781 as a vaginal
microbicide .
"Our work and that of others has shown that UC781 has low cytotoxicity in
vitro," they concluded. "We therefore feel that UC781 has excellent potential
for use in a retrovirucide or vaginal microbicide formulation, the first
nonnucleoside inhibitor of HIV-1 reverse transcriptase to present this
particular property."
This work was supported in part by Medical Research Council of Canada
grants PG-11089 and UI-13039.
The corresponding author for this study is Michael A. Parniak, Lady Davis
Institute for Medical Research, 3755 Cote Ste-Catherine Rd., Montreal,
Quebec H3T 1E2, Canada. Phone: (514) 340-8260. Fax: (514) 340-7502.
Email: mparniak@idi.jgh.mcgill.ca. - by Daniel J. DeNoon, Senior Editor
Copyright c 1997 Dow Jones and Compan |
