1st International Workshop on HIV Drug Resistance & Treatment Strategies


25-28 June 1997, St. Petersburg, Florida, USA


TWO NOVEL COMPOUNDS, A NON-NUCLEOSIDE RT INHIBITOR, UC-781, AND A BINDING/FUSION INHIBITOR, NSC 651016, ARE ACTIVE IN VIVO IN THE HuPBMC SCID MOUSE MODEL

Antiviral Therapy 1997;2 (Suppl 5):9 (abstract no. 9)

Michael A Ussery1, Owen L Wood1, Steven C Kunder1, Matthew A Bacho1, Dennis D Broud1, Susan F Papermaster1, Bradford E Hall1, Gary P Goldberg2, Melinda G Hollingshead3, John P Bader3 and Paul L Black1
1Food and Drug Administration, Rockville; 2AFFRI, Bethesda; and 3NCI, Frederick, Maryland, USA

PURPOSE: To define the in vivo antiviral activity of two novel compounds.

METHODS: SCID mice were reconstituted with human peripheral blood mononuclear cells (HuPBMC). After 2 weeks, these mice were infected with the A018 strain of HIV-1. Drug therapy was begun 1 day before infection. UC-781, a furanyl thiocarboxanilide that acts as a non-nucleoside RT inhibitor (NNRTI), was synthesized by Uniroyal Chemical. UC-781 was administered by gavage twice a day in doses of 5, 15, 50 and 150 mg/kg/day. NSC-651016 (Farmitalia) was administered i.p. daily or every other day at 300 mg/kg. Virus inhibition was measured by quantitative coculture of infectious HIV-1 and quantitative RNA viral load measurement (NASBA) on peritoneal wash cells, lymph nodes, spleen cells and plasma. Protection of CD4+ cells from virus-induced cytolysis was measured by FACS analysis.

RESULTS: UC-781 reduced titres of infectious virus by 2 logs in peritoneal cells and lymph nodes and reduced viral RNA copies as measured by NASBA 50-fold in peritoneal cells. NSC-651016, a binding/fusion inhibitor, reduced infectious virus and viral loads by more than 2 logs. NSC-651016 was more effective when given once a day rather than every other day. FACS analysis revealed protection of human CD4+ cells.

CONCLUSIONS: These compounds are interesting candidates for further drug development. NSC-651016 ranks as one of the most active compounds we have tested in the SCID model.

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1997-06-25
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