Synthetic mimetics of the CD4-binding site of HIV-1 gp120 are promising candidates for HIV-1 entry inhibition, as well as immunogen candidates for the elicitation of virus-neutralizing antibodies. On the basis of the crystal structure of gp120 in complex with CD4, we have used a recently introduced strategy for the generation of structurally diverse scaffolds to design and synthesize a scaffolded peptide, in which three fragments, making up the sequentially discontinuous binding site of gp120 for CD4, are presented in a nonlinear and discontinuous fashion through a molecular scoffold, which restrains conformational flexibility. The affinities of this molecule to CD4, as well as to the broadly neutralizing antibody mAb b12, whose epitope overlaps the CD4-binding site of gp120, were determined in competitive binding assays.
[Show abstract][Hide abstract] ABSTRACT: HIV/AIDS is one of the most serious public health challenges globally. Despite the great efforts that are being devoted to
prevent, treat and to better understand the disease, it is one of the main causes of morbidity and mortality worldwide. Currently,
there are 30 drugs or combinations of drugs approved by FDA. Because of the side-effects, price and drug resistance, it is
essential to discover new targets, to develop new technology and to find new anti-HIV drugs. This review summarizes the major
targets and assays currently used in anti-HIV drug screening.
[Show abstract][Hide abstract] ABSTRACT: This work was supported by the BioFuture Program (grant no. 0311882) of the German Federal Department of Education and Research (BMBF). 2D-sCD4 (cat. no. 7356) and mAb b12 (cat. no. 2640) were obtained through the NIH AIDS Research and Reference Reagent Program. We thank Christian Erck for preparing the immunogen conjugate.
[Show abstract][Hide abstract] ABSTRACT: The transmembrane protein gp130 acts as the signal transducing receptor subunit for interleukin-6 type cytokines, including viral interleukin-6, which is encoded by the Kaposi's sarcoma-associated herpes virus. Viral interleukin-6 has been shown to mimic human IL-6 functions, including activation of the JAK1 and STAT1/3 signaling pathways. Based on the crystal structure of three extracellular domains of gp130 in complex with viral interleukin-6, we have designed and synthesized a range of assembled peptides that mimic the sequentially discontinuous binding site of gp130 for viral interleukin-6. These peptides, which present the three binding site fragments of gp130 in a nonlinear, discontinuous fashion, were shown to inhibit the interaction of gp130 with viral interleukin-6, as well as the stimulation of viral interleukin-6-induced cell proliferation. These results validate the concept of synthetic mimicry of discontinuous protein-binding sites through assembled peptides, and the use of such molecules as modulators of protein-ligand interactions.
Chemical Biology & Drug Design 06/2008; 71(5):494-500. DOI:10.1111/j.1747-0285.2008.00649.x · 2.49 Impact Factor
Christoph G W Gertzen, Lina Spomer, Sander H J Smits, Dieter Häussinger, Verena Keitel, Holger Gohlke
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