Sequence driven interaction of amino acids in de-novo designed peptides determines c-Myc G-quadruplex unfolding inducing apoptosis in cancer cells

• Published in: Biochimica et biophysica acta. General subjects Vol. 1867; no. 2; p. 130267
• Main Authors: Banerjee, Nilanjan, Chatterjee, Oishika, Roychowdhury, Tanaya, Basu, Debadrita, Dutta, Anindya, Chowdhury, Madhurima, Dastidar, Shubhra Ghosh, Chatterjee, Subhrangsu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2023
• Subjects: Amino Acids; Apoptosis; C-MYC; G-quadruplex; G-Quadruplexes; Neoplasms; Peptide; Peptides - pharmacology; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc - genetics; C-MYC; Peptide; G-quadruplex
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130267

c-MYC proto-oncogene harbors a putative G-quadruplex structure (Pu27) at the NHEIII1 domain, which can shuffle between transcriptional inhibitor quadruplex and transcriptionally active duplex. In cancer cells this quadruplex destabilization is preferred and NHEIII1 domain assume a duplex topology thereby inducing c-MYC overexpression and tumorigenesis. Hence, the c-MYC quadruplex acts as an excellent target for anti-cancer therapy. Though researcher have tried to develop G-quadruplex targeted small molecules, work with G-quadruplex targeting peptides is very limited. Here we present a peptide that can bind to c-MYC quadruplex, destabilize the tetrad core, and permit the formation of a substantially different structure from the quartet core seen in the canonical G-quadruplexes. Such conformation potentially acted as a roadblock for transcription factors thereby reducing cMYC expression. This event sensitizes the cancer cell to activate apoptotic cascade via the c-MYC-VEGF-A-BCL2 axis. This study provides a detailed insight into the peptide-quadruplex interface that encourages better pharmacophore design to target dynamic quadruplex structure. We believe that our results will contribute to the development, characterization, and optimization of G-quadruplex binding peptides for potential clinical application. Schematic representation of the mode of action of CD23 peptide. [Display omitted] •Peptides act as an excellent ligands to arrest G-quadruplex structures. Its high specificity is coupled with low toxicity•c-Myc G-quadruplex targeted therapy can be manipulated to develop gene directed anticancer therapeutics.•G-quadruplex destabilization can be exploited to develop anticancer therapy.•There is no drug targeting c-Myc oncogene. NHE-III1 element has been shown to be a fantastic target for c-Myc suppression.