This application focuses on the development of a novel strategy for designing and delivery of peptide antigens for HIV vaccine. Specifically, it is proposed to develop new methodology for preparing and delivery of the ectodomain chemokine receptor mimetics as HIV vaccine candidate. The rationale for developing receptor mimetics as vaccine is based on the recent reports linking HIV infectivity, tropism, and AIDS progression to coreceptors which belong to the 7-transmembrane (TM), G protein-coupled receptor family and are activated by the chemokines. Reversible blockage of these coreceptors in vitro and individuals with homozygous defect in the coreceptor allele provide evidence of correlation of HIV resistance to HIV infection. It is hypothesized that vaccination with conformationally constrained peptidyl immunogens mimicking the extracellular surface ectodomain of these coreceptors may confer useful therapeutic or preventive intervention in HIV infectivity and AIDS progression. There are two major impediments in using these 7-TM coreceptors directly as immunogens for vaccination. These include their insolubility and low immunogenicity. The goals are to design and develop soluble mimetics of the extracellular domains of these 7-TM receptors as vaccination candidates, to verify and test the mimetics biochemically and structurally, and to develop a general strategy for immunization and delivery of the CC-R5 mimetics for eliciting high-titer antisera in small animals

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057145-03
Application #
6151208
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Chin, Jean
Project Start
1998-02-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2000
Total Cost
$283,121
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Tam, James P; Eom, Khee Dong (2005) Mimicking reverse protein splicing by three-segment tandem peptide ligation. Protein Pept Lett 12:743-9
Tam, J P; Yu, Q; Yang, J L (2001) Tandem ligation of unprotected peptides through thiaprolyl and cysteinyl bonds in water. J Am Chem Soc 123:2487-94
Chang, M S; Tam, J P; Sanders-Bush, E (2000) Dissecting intracellular signaling pathways with membrane-permeable peptides. Sci STKE 2000:pl1
Tam, J P; Wu, C; Yang, J L (2000) Membranolytic selectivity of cystine-stabilized cyclic protegrins. Eur J Biochem 267:3289-300
Miao, Z; Tam, J P (2000) Dehydropeptides from orthogonal ligation of unprotected peptides. Org Lett 2:3711-3
Tam, J P; Lu, Y A; Yang, J L (2000) Marked increase in membranolytic selectivity of novel cyclic tachyplesins constrained with an antiparallel two-beta strand cystine knot framework. Biochem Biophys Res Commun 267:783-90
Tam, J P; Lu, Y A; Yang, J L (2000) Design of salt-insensitive glycine-rich antimicrobial peptides with cyclic tricystine structures. Biochemistry 39:7159-69
Li, X; Zhang, L; Zhang, W et al. (2000) Solid-phase synthesis of 1,2,3, 4-tetrahydro-beta-carboline-containing peptidomimetics. Org Lett 2:3075-8
Tam, J P; Lu, Y A; Yang, J L et al. (1999) An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides. Proc Natl Acad Sci U S A 96:8913-8