Inhibitors and Probes of HIV-1 Cell Fusion

Bewley, Carole A.

Abstract

The Natural Products Chemistry Section, LBC, NIDDK has several ongoing projects whose long term aim is to identify and design inhibitors and probes of HIV-1 Envelope-mediated cell fusion. These include the design and development of new gp41-derived peptides and proteins that have dual functions as inhibitors and immunogens, discovery and high resolution structural characterization of new carbohydrate binding proteins that potently inhibit HIV-1 Entry through carbohydrate-mediated interactions with gp120/gp41, discovery of natural product inhibitors of HIV-1 fusion, and structural and mechanistic studies of HIV-1 Envelope - coreceptor interactions.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Type: Intramural Research (Z01)
• Project #: 1Z01DK032103-09
• Application #: 7734071
• Support Year: 9
• Fiscal Year: 2008
• Total Cost: $507,187

Institution

• Name: National Institute of Diabetes and Digestive and Kidney Diseases
• Country: United States

Publications

Bewley, Carole A (2008) Illuminating the switch in influenza viruses. Nat Biotechnol 26:60-2

Gustchina, Elena; Louis, John M; Lam, Son N et al. (2007) A monoclonal Fab derived from a human nonimmune phage library reveals a new epitope on gp41 and neutralizes diverse human immunodeficiency virus type 1 strains. J Virol 81:12946-53

Plaza, Alberto; Gustchina, Elena; Baker, Heather L et al. (2007) Mirabamides A-D, depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion. J Nat Prod 70:1753-60

Huang, Chih-Chin; Lam, Son N; Acharya, Priyamvada et al. (2007) Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317:1930-4

Gustchina, Elena; Louis, John M; Bewley, Carole A et al. (2006) Synergistic inhibition of HIV-1 envelope-mediated membrane fusion by inhibitors targeting the N and C-terminal heptad repeats of gp41. J Mol Biol 364:283-9

Plaza, Alberto; Bewley, Carole A (2006) Largamides A-H, unusual cyclic peptides from the marine cyanobacterium Oscillatoria sp. J Org Chem 71:6898-907

Mares, Jiri; Muller, Jan U; Skirgailiene, Audrone et al. (2006) A model for cell-surface-exposed carbohydrate moieties suitable for structural studies by NMR spectroscopy. Chembiochem 7:1764-73

Gutierrez-Lugo, Maria-Teresa; Newton, Gerald L; Fahey, Robert C et al. (2006) Cloning, expression and rapid purification of active recombinant mycothiol ligase as B1 immunoglobulin binding domain of streptococcal protein G, glutathione-S-transferase and maltose binding protein fusion proteins in Mycobacterium smegmatis. Protein Expr Purif 50:128-36

Williams Jr, David C; Lee, Jae Young; Cai, Mengli et al. (2005) Crystal structures of the HIV-1 inhibitory cyanobacterial protein MVL free and bound to Man3GlcNAc2: structural basis for specificity and high-affinity binding to the core pentasaccharide from n-linked oligomannoside. J Biol Chem 280:29269-76

Dimitrov, Antony S; Louis, John M; Bewley, Carole A et al. (2005) Conformational changes in HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion and inactivation. Biochemistry 44:12471-9