AEGiS-15IAC: Positional isomerism confers anti-HIV activity of some 4-hydroxycoumarine (4-hc) derivatives in cells culture.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Positional isomerism confers anti-HIV activity of some 4-hydroxycoumarine (4-hc) derivatives in cells culture.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. A10130)

Argirova R, Manolov I, Mladenova Z, Raleva S, Froloshka L, Savov A, Dundarova D
Fac. of Pharmacy, Med. Uni., Sofia, Bulgaria

BACKGROUND: Recently, a new class of integrase (IN) inhibitors has been an object of thorough study. Among them coumarine-based IN inhibitors with promising activity were found (Zhao, H. et al., 1997). It seemed perspectively to look for anti-HIV activity of newly synthesized or known 4-hydroxycoumarin (4-hc) derivatives.

METHODS: Seventeen 4-hc derivatives - 13 out of them known but never studied for anti-HIV activity and 4 newly synthesized were tested for anti-HIV activity in cell culture. Cell toxicity and anti-HIV assays were performed on MT-2 cells. HIV-1 induced syncytium formation in presence of the compounds, as well as their effect on HIV-1 production from chronically and acutely infected cells were studied. Reverse transcriptase (RT) activity using non-radioactive microtitre plate RT assay (HS-Lenti Kit-RT assay, Cavidi, Sweden) and cDNA synthesis (proviral DNA) by PCR in cells treated with the substances and appropriate controls were registered.

RESULTS: Three out of 17 4-hc derivatives were found to have anti-HIV activity in cell culture. They did not block syncytium formation, had no effect on viral life cycle after integration, showed low effect on virus replication through cDNA synthesis. All three substances were active against HIV-1 RT, predominantly by interference with binding of recombinant RT to the template-primer. The latter activity was demonstrated with concentrations at least 10 x higher than those showing antiviral effect and was not consistent with the observed anti-HIV activity in tissue culture.

CONCLUSIONS: All three 4-hc derivatives are positional isomers of di- and three-methoxy-4hc, which probably confers their anti-HIV-1 activity. Further studies are needed to clarify activity to another viral targets - i.e. against HIV-1 integrase.

Keywords: AEGIS, HIV, Acquired Immunodeficiency Syndrome, HIV Seropositivity, HIV-1, Virus Replication, HIV Integrase, HIV Integrase Inhibitors, RNA-Directed DNA Polymerase, Antiviral Agents, HIV Core Protein p24, Sweden, virology, immunology

040711
A10130