Research Project
2005330
Triangle Pharmaceuticals, Inc., a company focused on the development of antiviral compounds, has licensed the rights to the purine nucleoside analog (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), a prodrug for dioxolane guanosine (DXG), from Emory University to develop as a therapy for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To confirm and extend the anti-HIV activity of DAPD, this compound and related molecules will be tested against HIV in human lymphocytes, including human peripheral blood mononuclear (PBM) cell cultures. In addition, DAPD will be tested for activity against several clinical isolates of HIV in PBM cell cultures. The activity of DAPD, in combination (double and triple combinations ) with AZT, 3TC), (-)-FTC, d4T, ddI, ddI, ddC, a protease inhibitor such as Saquinavir, and a nonnucleoside reverse transcriptase inhibitor will be determined. HIV-1 resistant to other nucleoside analogs will be tested for cross resistance to DAPD. Moreover, the relative rate for the emergence of resistance to DAPD will be determined and compared with 3TC [or(-)-FTC] and AZT. The specific nucleotide changes that confer resistance to DAPD will be identified by passing virus in the presence of the active species, DXG. DAPD has demonstrated excellent in vivo efficacy in the woodchuck hepatitis B model. These results will be extended to HIV by evaluating the in vivo efficacy of DAPD using the HIV-infected xenotransplanted nude mouse model. The 5'-triphosphate of the active parent compound, DXG, will be synthesized and used to study the inhibition of the HIV-1 reverse transcriptase, the HBV DNA polymerase, and several human DNA polymerases. PROPOSED COMMERCIAL APPLICATION: Recent advances in the understanding of viral disease indicate that combination regimens directed against the virus have the potential to delay the development of viral resistance and potentially provide decades, rather than years, of benefit to HIV patients. These new regimens will be driven by the availability of new agents with a favorable toxicity profile. DAPD is a new chemical entity with potent HBV activity and has demonstrated excellent activity against HIV in preliminary tests. DAPD could be used in combination with other agents active against HIV and HBV to provide enhanced patient benefit and reduce the rate at which resistance develops.
