DRUGS BLOCKING BINDING OF TEMPLATE PRIMER DNA WITH HIV1

The overall objectives are the development of new antiviral drugs targeted to inhibit HIV-1 sites different from those targeted by currently available drugs. The specific aim of this proposal is to design compounds which inhibit the biding of HIV-1 RT with Template- Primer DNA (T-P DNA), a prerequisite step in HIV-1 replication. T- P DNA binds to a highly conserved region, 2 Helix H, of HIV-1 RT. Recently, a natural product 3,5,8-tribhydroxy-4- quinoline (THQ), from a marine sponge, was shown to inhibit the binding of T-P DNA with HIV-1 RT. However, THQ was unstable when exposed to air. In preliminary studies, the applicant has synthesized several carbocyclic analogs of THQ as lead compounds, which were more stable than THQ, and some of which were also more effective inhibitors of HIV-1 RT and of the replication of HIV-1 in lymphocyte cultures. This application describes the synthesis of isosteres and congeners of these lead compounds, the evaluation of their quantitative structure-activity relationships, and identification of the most promising drug candidates which may be effective against HIV-1, either per se, or in combination with currently available drugs. There is an excellent commercial potential for antiviral drugs for which escape mutants are less likely due to the highly conserved nature of the target. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 63 --PROJECT NUMBER......1 R43 AI40775-01 INVESTIGATOR NAME/ADDRESS FY 97 FURMAN, PHILLIP A IRG/INTRAMURAL UNIT..ZRG5 TRIANGLE PHARMACEUTICAL, INC AWARD AMOUNT......... $85,163 4611 UNIVERSITY DRIVE DURHAM, NC 27707 PERFORMING ORGANIZATION: TRIANGLE PHARMACEUTICALS, INC. TITLE MODIFIED PURINE NUCLEOSIDES AS ANTIVIRAL AGENTS ABSTRACT: 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.