SBIR-STTR Award

A synthetic peptide, DP-178, representing a discrete region of the HIV fusion protein, gp41, effectively blocks virus-mediated cell to cell fusion as well as de novo virus infection of T-cells (2). DP-178 has been shown to bind selectively to soluble forms of HIV-1 gp41 from which it was derived (4). While DP-178 is promising as a peptide therapeutic, it may exhibit a limited delivery profile characteristic of peptide therapeutics. Therefore, we seek to identify a small molecule mimic of DP-178, by exploiting the selective binding of this peptide to soluble forms of gp41. Our long term objectives are to discover and develop a novel class of antivirals for the treatment of HIV infection and AIDS. We will develop a high through-put biochemical screen based on the binding of DP-178 to gp41 analogs as a first step in identifying new antiviral leads.Our specific aims are(1) to develop an antibody-based biochemical binding assay suitable as a high through-put screen;(2) to develop a direct binding biochemical assay suitable as a high through-put screen;(3) to develop a cell-based gp41 binding and fusion assay suitable as a high through-put screen;(4) to identify sources of compounds for screening.National Institute of Allergy and Infectious Diseases (NIAID)

A synthetic peptide, T2O, representing a discrete region of the HlV fusion protein, gp4l, effectively blocks virus-mediated cell to cell fusion as well as de novo virus infection of T-cells. While T20 is promising as a peptide therapeutic, it could exhibit a limited delivery profile characteristic of peptide therapeutics. T20 binds selectively to soluble forms of HIV-1 gp4l from which it was derived. Using the screening assays developed in Phase I, we have identified more active peptides from which a T20 backup peptide will be chosen. In order to ultimately identify compounds having oral availability, we will use these screening assays to find a small molecule mimic of T2O inhibition of HIV-1 fusion and infection. The long term objectives of this proposal are to discover and develop a novel class of antivirals for the treatment of HIV infection and AIDS. We propose to develop a high through-put biochemical screen based on the binding of T20 to gp4l analogs as a first step in identifying new antiviral leads. Our specific aims are: (1) To select a second generation lead antiviral peptide with improved activity against HIV. (2) To screen a minimum of 100,000 additional compounds derived from highly diverse synthetic chemical libraries with automated antibody-based and direct binding assays. (3) To establish a partnership with at least one commercial entity possessing large diverse chemical and/or natural products libraries. (4) To determine antifusion activity of small molecule screening assay "hits" in viral and cell-based fusion assays. (5) To implement preclinical development plan after selection of lead peptide or small molecule compound(s).Proposed commercial application:The objectives set forth in this proposal are designed to identify a novel class of viral therapeutics targeted to HIV fusion which will have utility in the treatment of HlV infection in AIDS. Currently approved therapies for HIV infection target the viral RT and protease. Inhibitors of viral fusion would be mechanistically distinct from approved HlV antivirals and could find utility as both stand alone therapy and combination therapy with existing drugs.Thesaurus termsHIV envelope protein gp41, antiviral agent, cell fusion, chimeric protein, drug screening /evaluation, synthetic peptide biological product, chemical registry /resource, immunoglobulin, pharmacokinetics, recombinant protein Macaca fascicularis, enzyme linked immunosorbent assay, laboratory rat, peptide chemical synthesis, protein purificationNational Institute of Allergy and Infectious Diseases (NIAID)