AIDSWEEKLY Plus, November 6, 1995
Daniel J. DeNoon, Senior Editor

The new drugs inhibit HIV-1 but not HIV-2 reverse transcriptase and are therefore new members of the class of compounds known as non-nucleoside reverse transcriptase inhibitors (NNRTIs), report researchers Toshiaki Fujihashi of Jefferson Medical College, Philadelphia, Pennsylvania, and colleagues.

"The selective indices (toxic dose/effective dose) of these compounds were as high as >300 in some systems," Fujihashi et al. reported in the journal Antimicrobial Agents and Chemotherapy ("Anti-Human Immunodeficiency Virus (HIV) Activities of Halogenated Gomisin J Derivatives, New Nonnucleoside Inhibitors of HIV Type 1 Reverse Transcriptase," Antimic Ag Chem, September 1995;39(9):2000-7).

The new compounds are lignans, phenylpropanoid dimers found in many plants. Gomisins are family of dibenzocyclooctadiene lignans extracted from the fruit of Schizandra chinensis BAILL.

"There are various types of gomisins, A, B, C, D, E, F, G, J, and N; some possess central nervous system depressant, analgesic, antitussive, and/or calcium antagonist activities," Fujihashi et al. noted.

Some lignans have selective antiviral activities; it was reported in 1990 that dibenzylbutanolide lignans have anti-HIV activity (Schroder, H. et al., Z Naturforsch Sect C, 1990;45:1215-21). However, these compounds were too toxic for clinical use.

After screening more than 400 plant compounds, Fujihashi et al. found that (-)-gomisin J isolates had anti-HIV-1 activity. They developed new gomisin J derivatives that inhibited the virus at concentrations far lower than those toxic to cells.

"Among the various gomisin J derivatives tested for anti-HIV-1 activities in the MT-4 cell system, 4,9-dihalogenated gomisin J derivatives were found to be potent inhibitors (ED[50]s of 0.39 to 1.23 (micro)M) of HIV-1 induced cytopathicity," they reported. "The anti-HIV-1 activity of compound 1506 {(6R,7S, S-biar)-4,9,-dibromo-3,10- dihydroxy-1,2,11,12-tetramethoxy-6,7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclooctene} was 33-fold stronger than that of (-)-gomisin J."

Other derivatives - particularly compound 1580 which substituted iodine in place of bromine - were even more effective.

Experiments showed that the gomisin J derivatives inhibited HIV-1 reverse transcriptase but had no effect on HIV-2 or SIV. HIV-1 mutants resistant to the NNRTI nevirapine were cross-resistant to the gomisin J derivatives.

Rat studies showed that oral administration of compound 1506 could achieve serum concentrations in excess of antiviral concentrations without apparent toxicity.

"Together with the fact that AZT-resistant HIV-1 mutants are susceptible to gomisin J derivatives and that 1506 works synergistically with AZT, these observations suggest that further studies of gomisin J derivatives are warranted," Fujihashi et al. concluded.

The corresponding author for this study is Akira Kaji, Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076.

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