The broad, overall objectives of the proposed research are to develop a new methodology for the rational design of antiviral combinations with selective antiviral synergism between the components, and to develop a new anti-retroviral combination for the treatment of acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) which complements or supersedes existing treatments. The novel drug delivery methodology involves administering an antiviral agent in the form of two smaller prodrug molecules that combine to form the agent selectively at the target site.
The specific aims are: (1) to synthesize new aldehydes and acylhydrazides derived from Lucifer Yellow CH (LYCH), and to determine which of these accumulate optimally in monocyte lysosomes using fluorescence-activated cell sorting and high pressure liquid chromatography (HPLC); (2) to synthesize new suramin-like hydrazones with anti-retroviral activity against HIV and feline immunodeficiency virus (FIV) by combining the LYCH-derived aldehydes and acylhydrazides that accumulate in monocytes; (3) to screen these compounds to find hydrazones with greater anti- retroviral and greater cytotoxic activity than the aldehydes and acylhydrazides from which they were formed; and (4) to find an aldehyde + acylhydrazide combination that exhibits greater antiviral selectivity than the individual aldehyde, acylhydrazide, or preformed hydrazone due to selective antiviral hydrazone formation at the target (monocyte) relative to non-monocytic cells. Monocytes are a key reservoir for HIV, and protection of these cells from HIV (while sparing non-monocytic cells from cytoxicity) would be particularly important in the prevention of AIDS dementia. The Investigator has already obtained preliminary results relevant to each of these four specific aims, including synergistic anti-retroviral effects against HIV using an aldehyde + acylhydrazide combination, anti-retroviral effects in cell culture against HIV and FIV using LYCH hydrazones and related molecules, and hydrazone formation in whole animals and human monocytes.
