Structure-based design of a constrained peptide mimic of the HIV-1 V3 loop neutralization site.
Antigenic variation among different HIV-1 isolates has been a major problem in the development of an effective vaccine against AIDS. Peptide vaccines incorporating structural elements common to groups of viral isolates, such as the clade subtypes of HIV-1, hold promise; however, the design of such immunogens has been hampered by the lack of specific structural information on the viral proteins to be targeted. As part of a structure-based approach to this problem, we report the design and characterization of a conformationally restricted peptide analog (Aib142) of a highly conserved HIV-1 clade-B sequence from the third variable loop of the membrane glycoprotein gp120. The design strategy incorporates peptide conformational data derived from crystal structure analysis of an MN-isolate peptide (RP142) in complex with the Fab fragment (Fab59.1) of a broadly neutralizing antibody. The synthetic peptide (Aib142) replaces an alanine residue within the V3 loop epitope sequence GPGRAF by the conformationally restricted helicogenic alpha-aminoisobutyryl residue. As expected, the crystal structure of the Fab 59.1-Aib142 complex at 2.8 A resolution shows that the peptide interacts very similarly with the neutralizing antibody. Proton nuclear magnetic resonance (NMR) studies indicate that the free Aib142 peptide is indeed more ordered in solution with a conformational preference that corresponds to the X-ray structure of its Fab-bound form. Aib142 thus represents the first step in the design of conformationally constrained peptide analogs built to mimic biologically relevant structural forms of HIV-1 neutralization sites.
Ghiara
J B
JB
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Ferguson
D C
DC
Satterthwait
A C
AC
Dyson
H J
HJ
Wilson
I A
IA
D016915:AIDS Vaccines; D000595:Amino Acid Sequence; D000621:Aminoisobutyric Acids; D000940:Antigenic Variation; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007140:Immunoglobulin Fab Fragments; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology; D011487:Protein Conformation
D016915:AIDS Vaccines; D000621:Aminoisobutyric Acids; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D010455:Peptides