Any step in replication of the human immunodeficiency virus type 1 (HIV-1) could potentially serve as a target for antiviral chemotherapy. Thus, antiviral agents could be aimed at HIV-1 proteins essential for virus replication, including viral structural and non-structural proteins and products of HIV-1 regulatory genes. Anti-HIV-1 chemotherapeutic agents targeted to HIV-1 reverse transcriptase and protease have been the most extensively investigated. Efforts to develop protective immunogens against HIV-1 resulted in the delineation of regions on env glycoproteins gpl2O and gp4l critical for infection. These regions include: the principal neutralizing determinant located on the V3 hypervariable loop of gpl2O; domains on gpl2O comprising the CD4 binding site; the fusion domain of gp41; and sites on gpl2O/gp4l involved in oligomerization of env glycoproteins, i.e., in virus assembly. These functionally important sites, recognizable by antibodies with appropriate specificity, represent also potential targets for chemotherapy. Indeed, compounds inhibiting the reaction between the V3 hypervariable loop and anti-V3 specific antibodies were discovered. The majority (about 67%) of substances inhibiting this antigen-antibody interaction also inhibited the replication of HIV-1 in both T-lymphocytic and promonocytic cell lines. Thus, a rapid prescreening method for compounds with anti-HIV-1 antiviral activity based on radioimmunoassays or enzyme-linked immunoadsorbent assays was discovered. Most of these compounds inhibited the reaction between V3 loops from distinct HIV-1 isolates (clones), differing greatly in primary amino acid sequence, and the corresponding antibodies. The goals of the proposed research are: (1) selection of additional antiviral compounds specific for the V3 hypervariable loop having (a) high antiviral activity against many HIV-1 isolates, and (b) low cytotoxicity; (2) Definition of structure-function relationships for compounds with antiviral activity directed against V3 loops, leading to the rational design of drugs with improved activity; (3) Demonstration of activity of these compounds against primary HIV-1 isolates in peripheral blood lymphocytes and monocytes; (4) Design of compounds with reactive groups leading to their irreversible binding to HIV-1 glycoproteins and thus to potentiation of antiviral activity; (5) Design of additional antiviral compounds targeted to regions on HIV-1 envelope glycoproteins other than the V3 loop; (6) Assessment of antiviral activity of these compounds when combined with antiviral drugs targeted to sites other than gpl2O/gp4l, for example, 3'-azido-2'-3'-dideoxythymidine (AZT); (7)To study in greater detail the effect of these compounds on steps in HIV-1 replication; (8) Search for the emergence of HIV-1 mutants resistant to the aforementioned compounds. Accomplishment of these goals is expected to lead to improved combined therapy, and possibly prophylaxis of HIV-1 infections.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043315-08
Application #
2091161
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1989-11-07
Project End
1996-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Seppala, M; Jiang, S; Strick, N et al. (1997) Glycodelins GdA and GdS modified by 3-hydroxyphthalic anhydride inhibit gp120-CD4 binding and HIV-1 infection in vitro. Lab Invest 77:127-30
Neurath, A R; Li, Y Y; Strick, N et al. (1996) A herpesvirus inhibitor from bovine whey. Lancet 347:1703-4
Neurath, A R; Jiang, S; Strick, N et al. (1996) Bovine beta-lactoglobulin modified by 3-hydroxyphthalic anhydride blocks the CD4 cell receptor for HIV. Nat Med 2:230-4
Jiang, S; Lin, K; Strick, N et al. (1996) Chemically modified bovine beta-lactoglobulin blocks uptake of HIV-1 by colon- and cervix-derived epithelial cell lines. J Acquir Immune Defic Syndr Hum Retrovirol 13:461-2
Neurath, A R; Debnath, A K; Strick, N et al. (1995) Blocking of CD4 cell receptors for the human immunodeficiency virus type 1 (HIV-1) by chemically modified bovine milk proteins: potential for AIDS prophylaxis. J Mol Recognit 8:304-16
Neurath, A R; Lin, K; Strick, N et al. (1995) Two partially overlapping antiviral peptides from the external portion of HIV type 1 glycoprotein 41, adjoining the transmembrane region, affect the glycoprotein 41 fusion domain. AIDS Res Hum Retroviruses 11:189-90
Neurath, A R; Strick, N; Debnath, A K (1995) Structural requirements for and consequences of an antiviral porphyrin binding to the V3 loop of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp120. J Mol Recognit 8:345-57
Neurath, A R; Strick, N; Lin, K et al. (1995) Multifaceted consequences of anti-gp41 monoclonal antibody 2F5 binding to HIV type 1 virions. AIDS Res Hum Retroviruses 11:687-96
Debnath, A K; Jiang, S; Strick, N et al. (1994) Three-dimensional structure-activity analysis of a series of porphyrin derivatives with anti-HIV-1 activity targeted to the V3 loop of the gp120 envelope glycoprotein of the human immunodeficiency virus type 1. J Med Chem 37:1099-108
Jiang, S; Lin, K; Strick, N et al. (1993) Inhibition of HIV-1 infection by a fusion domain binding peptide from the HIV-1 envelope glycoprotein GP41. Biochem Biophys Res Commun 195:533-8

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