GOSSYPOL DERIVATIVES AS COVALENT CARRIERS OF ANTIVIRALS

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The objective of this research project is to develop new antiviral drugs useful for treatment of disease caused by enveloped viruses. Included among these diseases is Acquired Immunodeficiency Syndrome. The rationale for the proposed approach is to utilize intrinsic properties of gossypol derivatives as antiviral agents against enveloped viruses and as agents with affinities for the envelope membranes. Gossypol derivatives will be convalently attached to known antiviral drugs in order to develop a new set of drugs in which the gossypol moiety is both a vehicle for drug delivery and a separate drug which may exert a synergistic effect after hydrolysis of the covalent adduct of gossypol derivative and antiviral drug. The specific aims are: 1) The esterify gossypol derivatives to promising antivirals against human immunodeficiency virus (HIV) and herpes simplex virus (HSV), such as aziodothymidine, ribavirin and acyclovir, and to test these conjugated derivatives for activity in vitro. 2) To attach gossypol derivatives to polypeptides which are known to be active against HIV or influenza virus, and to test these conjugated derivatives for activity in vitro. The major methodology in this study is the synthetic chemistry necessary to prepare various gossypol derivatives and to attach derivatives to known antivirals. Much of this synthetic chemistry has been developed already. In vitro studies of these new drugs will be carried out with HIV, using human T cells; with HSV-II, using Vero cells; and with influenza virus, using MDCK cells. This approach, which utilizes a retrovirus, a DNA virus, and an RNA virus, all of which are enveloped, should provide an indication whether these new covalently linked drugs are generally active against enveloped viruses or whether they exhibit specificity for certain enveloped viruses.