SFB796 - Sub project A5
(sub project concluded on Dec 31 2012)

Suche


Exploration of the structural basis for the functional mimicry of the CD4 binding site of HIV-1 gp120: Implications vor virus entry inhibition and the induction of broadly neutralizing antibodies

 

Project summary

Entry of the virus HIV-1 into its host cell is initiated by specific interaction of the viral envelope glycoprotein gp120 with the cellular receptor CD4. The binding site of gp120 for CD4 (CD4bs) represents a conserved region in this otherwise highly variable protein. Furthermore, the epitope of the broadly neutralizing anti-HIV-1 antibody mAb b12 has been found to overlap the CD4bs. Molecules capable of structurally and functionally mimicking this gp120 region are therefore promising candidates as HIV-1 entry inhibitors, as well as immunogens for the elicitation of virus-neutralizing antibodies.
Based on the crystal structure of core gp120 in complex with CD4, we have previously designed molecules, which present the gp120 fragments that constitute its CD4bs. Immunization with such a CD4bs mimetic peptide, which competes with gp120 for binding to CD4 and mAb b12, respectively, yielded antibodies that recognize gp120 with a specificity related to that of mAb b12.
The goal of this project, which will be carried out in collaboration with U. Schubert and Y. Muller (projects A1 and Z), is to understand the structural features of CD4bs mimetics that govern their affinity to CD4, which will in turn guide the design of improved, specific CD4bs mimetics as entry inhibitors, as well as immunogen candidates for the elicitation of broadly neutralizing anti-HIV-1 antibodies. The overall question we will address is whether such mimetic molecules are able to adopt structures that resemble the CD4bs within the structural context of gp120, and whether this structural analogy correlates with the affinity to CD4. This will be accomplished by structural analysis of a range of different CD4bs mimetic molecules in complex with CD4. In a complementary approach, we will design and generate synthetic mimetics of the gp120 epitope for mAb b12, which, while overlapping the CD4bs, has recently been shown to also involve gp120 regions that are not part of the CD4bs.

Structure-based mimicry of the CD4 binding site of HIV gp120 through a synthetic peptide.

 

Project relevant publications

  • Eichler, J.   (2008).   Peptides as protein binding site mimetics.   Curr Opin Chem Biol 12, 707-713.

  • Sudarman, E., Bollati-Fogolin, M., Hafner, M., Müller, W., Scheller, J., Rose-John, S. and Eichler, J.   (2008).   Synthetic Mimetics of the gp130 Binding Site for Viral Interleukin-6 as Inhibitors of the vIL-6 – gp130 Interaction.   Chem Biol Drug Des 71, 494-500.

  • Franke, R., Hirsch, T., Overwin, H. and Eichler, J.   (2007).   Synthetic Mimetics of the CD4 Binding Site of HIV-1 gp120 for the Design of Immunogens.   Angew Chem Int Ed 46(8), 1253-1255.

  • Hunke, C., Hirsch, T. and Eichler, J.   (2006).   Structure-Based Synthetic Mimicry of Discontinuous Protein Binding Sites: Inhibitors of the Interaction of Mena EVH1 Domain with Proline-Rich Ligands.   Chem Bio Chem 7(8), 1258-1264.

  • Franke, R., Doll, C. and Eichler, J.   (2005).   Peptide ligation through click chemistry for the generation of assembled and scaffolded peptides.   Tetrahedron Lett 46(26), 4479-4482.