3,5,8-TRIHYDROXY-4-QUINOLONE, A NOVEL NATURAL INHIBITOR OF THE REVERSE TRANSCRIPTASES OF HUMAN IMMUNODEFICIENCY VIRUSES TYPE-1 AND TYPE-2

The natural product of the Red Sea sponge Verongia sp., identified as 3,5,8-trihydroxy-4-quinolone, was found to be a potent inhibitor of th e RNA-directed DNA synthesis of the reverse transcriptases (RTs) of hu man immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2, respe ctively). This inhibition was unaffected by the nature of the primer t emplate used for DNA synthesis. The DNA-dependent DNA polymerase activ ity was inhibited to a lesser extent, whereas the ribonuclease H (RNas e H) function associated with both HIV RTs was only slightly inhibited . The inhibition by the trihydroxyquinolone is reversible and noncompe titive with respect to both substrates-dTTP and the template primer po ly(rA)(n).oligo(dT)(12-18). The inhibitor binds HIV-1 RT with a high a ffinity (K-i = 0.46 mu M). This compound was shown also to inhibit the catalytic activities of the RT of murine leukemia virus, establishing the general inhibitory effect on retroviral RTs. Introductions of ace tyl or methoxy moieties at positions with potential activity have gene rated three synthetic analogs of the natural compound. Only one analog , 5,8-dimethoxy-4-quinolone, exhibited an inhibition potency similar t o that of the unmodified compound. Analysis of the three analogs has l ed us to the conclusion that the hydroxyl group at the ortho position to the carbonyl group in the pyridinone ring is a key structural eleme nt for the inhibitory activity. Thus, it could well be that the inhibi tor interacts with the enzyme through a hydrogen bond of this hydroxyl group. We hope that the identification of the inhibitory site of the compound might be an important step toward the rational design of new potent anti-HTV RT drugs. (C) 1994 Academic Press, Inc.