Research Project
6040611
DESCRIPTION: (Adapted from Applicant's Abstract) More effective therapies need to be developed to treat infections by human immunodeficiency virus (HIV), which has caused the pandemic of acquired immune deficiency syndrome (AIDS). At present, HIV-infected patients can be treated with the clinically available anti-HIV drugs for only limited periods of time because of their toxic side effects and the ability of HIV to develop resistance to these drugs. The bis(naphthalenyltetrahydroisoquinoline) alkaloid, michellamine B is a new therapeutic candidate for the treatment of this disease. This natural product not only inhibits the replication of HIV types 1 and 2 in human T lymphocytes in cell culture but also inhibits the replication of HIV-1 strains that are resistant to the currently available anti-HIV nucleoside drugs. Because of the anti-HIV activity of michellamine B in cell culture and its low toxicity in two animal models, the National Cancer Institute is currently conducting pharmacological and toxicological studies in preparation for Phase 1 clinical trials. The applicants propose a structure-activity study on analogs of michellamine B to determine the pharmacophoric groups required for antiviral activity and their optimal spatial orientation. This information will then permit the design and synthesis of analogs that are more synthetically accessible than michellamine B and have a more favorable therapeutic index. In addition, evaluation of these analogs should provide valuable information on the mechanism of antiviral action of the michellamines. The two analogs of michellamine B designed and synthesized in preliminary studies inhibited the cytopathic effect of HIV- 1 (HTLV-IIIB strain) in the human lymphoblastoid cell line CEM-SS. Both analogs inhibited recombinant HIV reverse transcriptase, an indication that inhibition of this enzyme may be one of the mechanisms for their anti-HIV activity. Both also inhibited the activity of protein kinase C. Therefore, inhibition of the phosphorylation of an essential viral protein may be another mechanism of action.
