Executive Summary : | G-quadruplexes (GQs) are one of the stable secondary structures of nucleic acid. It is usually formed by the guanine rich nucleic acid sequences. It is implicated in many essential cellular processes such as regulation of DNA replication, transcription, translation, RNA localization and in many others. In the human genome, guanine-rich sequences with the potential to form GQs exist in the telomere as well as in promoter regions of various oncogenes. The biological functions associated with GQs make these structures as appealing targets for drug development. It has been found that the telomerase enzyme is over-expressed in approximately 85% of cancer cells and also plays important role in cell immortalization. The activity of telomerase enzyme is inhibited if the single-stranded telomeric nucleic acid sequences fold into a quadruplex. Moreover the stabilization of telomeric GQs also leads to apoptosis in malignant cells. In addition, stabilization of GQs at the promoter sites provides a potential means to modulate the transcription of oncogenes. That is why the GQs, those particularly formed at the human telomere and at promoter sites of oncogenes, have become attractive cancer-specific molecular targets for anticancer therapeutics. Significant concern has been seen in recent years to develop GQ interactive small molecules. Till date various small molecules like planar aromatic compounds, metal complexes, various naturally occurring compounds have been reported which can interact and stabilize the GQs. But peptides are really less explored towards this end. There are several advantages of using peptides for targeting GQs including trouble-free synthetic methodology and purification, cell permeability, tumor-penetrating ability, and improved biocompatibility. Moreover, peptides don’t accumulate in specific organs like kidney or liver as it easily degrades into the naturally occurring amino acid residues which help to reduce the toxic side effects. Here, it is proposed to develop peptide / peptide based molecules to target GQs of human telomere and promoter region of oncogenes. Various biophysical and biochemical techniques would be applied for the purpose. Afterwards the cytotoxicity of the peptides would be addressed by both the dose and time dependent MTT cell viability assay on cancer cells and normal cells. Finally the telomerase repeat amplification protocol (TRAP) assay would be performed to check whether the designed peptide can inhibit the activity of telomerase enzyme. |