| Recently, the number of bacterial strains that have acquired resistance to antibiotics through either genetic mutations or genetic exchange has risen at an alarming rate. As a result, many antibiotics that were capable of treating bacterial infections in the past are currently not viable, giving rise to the need for a new class of drugs. Using a set of established criteria for peptides of antimicrobial function, our lab designed a novel amphiphilic hexapeptide that was the focus of my initial research. It was envisioned that the hexapeptide would first be synthesized and then tested for cytotoxicity. Due to steric constraints within the system, however, the project was not seen to fruition.; In light of these complications, the focus of my research moved from novel peptides to that of natural ones derived from commercially available amino acids. While it appears to be simple in nature, the amino acid sequence of a peptide carries a wealth of information, both structural and functional. Without such specificity, the number of possible conformations for some random polypeptide chain is practically limitless. As a result, structure determinations from sequence are highly unpredictable.; In order to circumvent this "folding problem," Mutter and Vuilleumier proposed the idea of assembling amphiphilic peptides atop a template molecule with the capacity to fold the peptides into their desired secondary structure, a strategy referred to as the TASP concept. Using this approach, our lab designed its own template-assembled synthetic protein. Amphiphilic peptides were sequenced specifically for folding into alpha-helical conformations, which would then be cross-linked to the template beta-cyclodextrin. While stepwise solid-phase synthesis afforded the specific peptide sequences, purification by HPLC proved to be very difficult. At the same time, a new class of compounds was synthesized in our laboratory with the potential for use in biological applications. Due to the inefficiency of purification, a different project was begun in order to realize the biological significance, if any, of the new compounds.; It was hypothesized that our new folding oligomers may be potential binders of the G-quadruplex structure. It is this conformation that is believed to inhibit the enzyme telomerase from replicating the telomere. While normal somatic cells lack telomerase activity, the enzyme is activated in cancer cells, enabling them to grow indefinitely. Based on this finding, one of the most promising approaches in cancer therapeutics is the development of compounds for stabilization of the G-quadruplex as a means to inhibit telomerase. (Abstract shortened by UMI.)... |
