Highly Potent and Selective Inhibition of HIV-1 Replication by a Novel Series of 6-Substituted Acyclouridine Derivatives [International Conference on AIDS (7th: 1991: Florence, Italy)]

Press Release at the VII International Conference on AIDS
Presentation number: TU.A.63
Abstract title: Highly potent and selective inhibition of HIV-1
replication by a novel series of 6-substituted
acyclouridine derivatives.
Authors: Masanori BABA1, S. Shigetal, E. De Clercq2, H. Tanaka3
-.6 4 45
T. Miyasaka M. Ubasawa, K. Umezu, R.T. Walker5
Affiliation of authors: Department of Bacteriology, Fukushima Medical College, Fukushima, Japan, 2Rega Institute, K.U.
Leuven, Leuven, Belgium, Showa University, Tokyo Japan,
4Mitsubishi Kasei Corporation, Yokohama, Japan, University of Birmingham, Birmingham, UK.
Although a number of compounds have been shown to inhibit the
replication of human immunodeficiency virus type 1 (HIV-1), azidothymidine (AZT) is still only drug that has been licensed for clinical use in the treatment of AIDS. AZT treatment leads to an improvement of the clinical symptoms and prolongation of the survival of patients with AIDS. However, the usefulness of AZT is limited by serious side effects such as bone marrow suppression or emergence of AZTresistant HIV-1 variants. Therefore, it is mandatory to develop new
compounds with potent activity, reduced toxicity, and, preferably, a
different mechanism of action.
Our continuous efforts being made to find effective chemotherapeutic agents against HIV-1 have recently borne the 6-substituted
acyclouridine derivative 1-[2-(hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as a new lead for anti-HIV-1 agents [1]. HEPT is a
unique compound, in that it is only inhibitory to HIV-1. HIV-2 and
other animal retroviruses are insensitive to HEPT [2]. Following the
HEPT lead, we have designed more than 200 HEPT derivatives and examined for their inhibitory effects on HIV-1 replication in a variety
of cell systems. More than 20 compounds have been shown to inhibit
HIV-1 replication within the nanomolar concentration range [3,4].
Among the compounds, 5-ethyl-l-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil (E-EBU-dM) is the most potent and selective inhibitor of
HIV-1 [5]. Its 50Z antivirally effective concentrations for MT-4
cells and peripheral blood lymphocytes were 2.2 and 0.45 nM, respectively. These concentrations were more than 100,000 times lower than
the 50Z cytotoxic concentrations. E-EBU-dM was equally inhibitory to
some clinical isolates of HIV-l, including an AZT-resistant variant.
However, like HEPT, E-EBUJ-dM did not inhibit HIV-2 replication. Studies on the mechanism of action have revealed that the HEPT derivatives act specifically on HIV-l reverse transcriptase, according to a
mechanism that is different from that of AZT or dideoxynucleosides.
Furthermore, the HEPT derivatives may share a similar mechanism of
action with the anti-HIV-1 benzodiazepine derivatives (TIBO and BIRG-587] that have recently been reported as highly potent and specific inhibitors of HIV-l [6,7].
In conclusion, a novel series of HEPT derivatives is a promis
ing candidate for anti-AIDS chemotherapy. Studies on their pharmacokinetics, metabolic disposition, and toxicology are now in progress
in order to select the best candidate for its clinical trials in patients with AIDS.
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