ABSTRACT
An important goal of structural biochemistry is the reduction of complex molecules to small functional units that are amenable to high-resolution structural analysis and rapid modification. The dissection of multidomain proteins into small synthetic conformationally restricted components is an important step in the design of low-molecular-weight nonpeptides that mimic the activity of the native protein. Mimetics of critical functional domains might possess beneficial properties in comparison to the intact proteinaceous species with regard to specificity and therapeutic potential, and are valuable probes for the study of molecular recognition events.
Subject(s)
Drug Design , Genes, Immunoglobulin , Peptides , Protein Conformation , Recombinant Fusion ProteinsABSTRACT
Poor bioavailability, rapid degradation, antigenicity, and high cost often limit the use of proteinaceous pharmaceuticals. One goal of structural biochemistry is the reduction of complex molecules to small functional units that are amenable to high-resolution structural analysis and rapid modification. The dissection of complex proteins into small synthetic conformationally restricted components is an important step in the design of low molecular weight nonpeptides that mimic the activity of the native protein. We have developed a reverse-turn mimetic system to explore peptide and protein structure-function relationships. We now report the design and synthesis of a small molecule (M(r) 810, as its trifluoroacetate salt), water soluble, proteolytically stable mimetic of residues Gln40-Thr45 of the complementarity-determining 2-like region of CD4. This mimetic has a low micromolar Kd for human T-lymphotropic virus type IIIB gp120 and reduces syncytium formation.
Subject(s)
CD4 Antigens/chemistry , CD4-Positive T-Lymphocytes/microbiology , HIV Envelope Protein gp120/metabolism , Binding, Competitive , CD4 Antigens/metabolism , Cell Fusion , Cells, Cultured , Drug Design , Humans , In Vitro Techniques , Models, Molecular , Molecular Structure , Protein ConformationABSTRACT
A technique for producing non-peptide compounds (mimetics) of designed specificities was developed that permitted the synthesis of a conformationally restricted molecule that mimicked the binding and functional properties of monoclonal antibody (MAb) 87.92.6, which recognizes the reovirus type 3 cellular receptor. Binding of either MAb 87.92.6, peptide analogs, or 87.1-mimetic to the cellular receptor inhibited cellular proliferation. The mimetic was a synthetic beta-loop structure that mimics the second complementarity-determining region of the MAb. These studies may lead to strategies for the synthetic design of antibody complementarity regions, ligands, and other pharmacologically active agents that are water soluble, resistant to proteolysis, and nonimmunogenic.