Peptide and protein interactions clearly play essential roles in a huge number of biological processes. The design of peptidomimetics that can reproduce these interactions has therefore been a central endeavor in the fields of medicinal chemistry, molecular recognition, and in the emerging field of chemical genetics. A successfully designed peptidomimetic can serve as a molecular probe for the study of receptor function and can potentially be developed as a therapeutic agent. Unfortunately, the design of peptidomimetics is complicated by a number of factors. One serious factor is that it is generally not possible to determine the exact bioactive conformation of most peptides. A second key problem is that predictions of binding interactions in aqueous solution are often not accurate. Therefore, there is a high degree of uncertainty even in the best of peptidomimetic designs. Consequently, the identification of a potent, bioactive peptidomimetic generally requires the time consuming and labor intensive iterative synthesis and evaluation of multiple compounds. We propose general strategies to expedite the development of bioactive peptidomimetics by integrating library synthesis and evaluation into the peptidomimetic design process. In the prior grant period we demonstrated the potential of this approach by developing the first method for generating libraries of small molecule peptidomimetics based upon the beta-turn structure, which is one of the three major secondary structural elements of peptides and proteins and plays a key role in many recognition events in biological processes. Screening these peptidomimetic libraries has resulted in the identification of ligands to a number of therapeutically relevant receptor targets. Here we propose to even more effectively integrate library approaches with peptidomimetic design. First, we will further develop heterocycle libraries based upon the structure of the beta-turn. Second, we will use library approaches integrated with design strategies to develop mimetics of the alycopeptide antibiotic vancomycin that bind to the modified peptidoglycan precursor N-acyl-L-Lys-D-Ala-D-Lactate present in vancomycin resistant bacteria. The successful development of peptidomimetics that bind N-acyl-L-Lys-D-Ala-D-Lactate potentially could serve as therapeutic agents for the treatment of vancomycin resistant bacterial infections.
|Ahrendt, Kateri A; Olsen, Jacob A; Wakao, Masahiro et al. (2003) Identification of potent and broad-spectrum antibiotics from SAR studies of a synthetic vancomycin analogue. Bioorg Med Chem Lett 13:1683-6|