PEYSSONOL-A AND PEYSSONAL-B, 2 NOVEL INHIBITORS OF THE REVERSE TRANSCRIPTASES OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AND TYPE-2

Two new sesquiterpene hydroquinones, peyssonol A and peyssonol B, of t he Red Sea algae Peyssonelia sp., have been shown to be potent inhibit ors of the RNA-directed DNA synthesis of the reverse transcriptases (R Ts) of human immunodeficiency virus (HIV)-1 and HIV-2, The DNA-depende nt DNA polymerase activity is inhibited to a lesser extent, whereas th e RNase H activity is unaffected. The inhibition of the DNA polymerase activities is independent of the nature of the template primers used, Peyssonol A probably binds the RT at a site distinct from those occup ied by the substrates of the RNA-directed DNA synthesis, since the mod e of inhibition is noncompetitive with respect to both dNTP's and temp late primer. This is partially true for peyssonol B, which is noncompe titive with respect to only dNTP, but is competitive with respect to t he template primer, We have speculated that, since peyssonol B and the template primer bear no apparent structural resemblance, the competit ive pattern of inhibition can be explained by an indirect steric hindr ance or by the overlap of the inhibitor and the substrate distinct bin ding sites of the enzyme. Alternatively, the binding of the inhibitor to a distinct site induces conformational changes that distort the bin ding of the template primer. Furthermore, we have shown that both peys sonol A and peyssonol B interfere with the direct binding of the RT to the template primer, offering an explanation for the mechanism of the enzyme inhibition. The insensitivity of DNA polymerase beta and the p oor response of DNA polymerase alpha to peyssonol A make this inhibito r more attractive for the future development of a potent anti-HIV RT d rug. (C) 1995 Academic Press, Inc.