Cyclic V3-loop-related HIV-1 conjugate vaccines. Synthesis, conformation and immunological properties.
Branched undecapeptides with sequences related to the virus glycoprotein V3 domain sequences of the MN and IIIB variants of HIV-1 were synthesized and cyclized with a peptide (amide) closure to cyclic decapeptides. Two-dimensional NMR studies allowed protons for the MN variant-related cycle (L-697,250) to be assigned. Molecular modelling with distance geometry methods permitted a conformation to be identified which showed good agreement with ROESY and 2D NMR study data. A molecular dynamics simulation showed that the highly conserved loop tip sequence (Gly-Pro-Gly-Arg) was in a conventional beta-turn less than 50% of the time. For evaluation of immunogenicity and antibody characterization studies, covalent carrier conjugates were prepared. 3-Maleimidopropionylation of the Nle amino group of the cyclic peptides gave an electrophilic tether which captured a thiol group from a thiolated carrier protein, OMPC (outer membrane protein complex of Neisseria meningitidis). Through the use of a novel co-conjugation procedure, soluble immunogen-carrier molecules were prepared which had suitable physical properties for use as a vaccine. These V3-loop-based vaccines could elicit neutralizing antibody, but not consistently in all animals. Characterization of sera showed that responses were broadly virus neutralizing.
Tolman
R L
RL
Merck Research Laboratories, Rahway, New Jersey.
Bednarek
M A
MA
Johnson
B A
BA
Leanza
W J
WJ
Marburg
S
S
Underwood
D J
DJ
Emini
E A
EA
Conley
A J
AJ
D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology*; D011817:Rabbits; D014614:Vaccines, Synthetic / Q000276:immunology*
D016915:AIDS Vaccines; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D014614:Vaccines, Synthetic