bi052615k_si_001.pdf (19.31 kB)

Stabilization of the Biologically Active Conformation of the Principal Neutralizing Determinant of HIV-1IIIB Containing a cis-Proline Surrogate:  1H NMR and Molecular Modeling Study

Download (19.31 kB)
journal contribution
posted on 04.04.2006, 00:00 by Julian Garcia, Pascal Dumy, Osnat Rosen, Jacob Anglister
The V3 loop is part of the gp120 glycoprotein, an extracellular protein located on the membrane of the human immunodeficiency virus (HIV-1). This loop is significantly important in many biological processes of the virus and contains the principal neutralizing determinant (PND). The PND is one of the most variable regions of the envelope, and this is probably related to the ability of the HIV virus to escape the immunologic defenses of the target host. Particular attention has been paid to the central part of the V3 loop which contains a highly conserved GPGR/GPGQ sequence and represents the binding site for antibodies. Many attempts have been made to design synthetic peptides as mimics of the V3 loop capable of eliciting immune response. However, this strategy suffers from the great conformational flexibility small peptides have in solution, which together with bioavailability represents the most important limitation to the usefulness of synthetic peptides as drugs and as synthetic immunogens. The use of conformationally constrained peptides can alleviate this problem. Early works using NMR studies have shown that a V3IIIB loop-derived peptide is conformationally heterogeneous when free in water. Upon complexation with 0.5β, a monoclonal neutralizing antibody specific for the HIV-1IIIB strain, it adopts a β-hairpin conformation with the central proline forming a type VIb β-turn. In this study, we report the design and characterization of a conformationally restricted peptide with a sequence identical to that previously described, but with thiazolidine derivatives replacing the proline. The affinity of the 2,2-dimethylthiazolidine derivative for 0.5β demonstrates that this moiety can successfully be used to mimic the proline in a cis conformation. This peptide not only displays a high propensity to adopt a β-hairpin conformation but also retains the type VIb RGPG β-turn similar to that found in the native complex. These compounds could help in elaborating more efficient immunogens for HIV-1 synthetic vaccine development.

History

Exports