Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Peptide-based inhibitors for targeting telomerase-active cancers (#113)

Reginald Young 1 , Alexander P Sobinoff 2 , Hilda Pickett 2 , Yu Heng Lau 1
  1. School of Chemistry, The University of Sydney, Sydney, NSW, Australia
  2. Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia

Telomeres are important nucleoprotein structures capping the ends of chromosomes that act as a form of protection against DNA replication errors. However, telomere attrition is inevitable with each iteration of chromosome replication, resulting in replicative senescence and eventual cell death.1 Cancers have developed methods to maintain their telomeric DNA in order to avoid cell death from replicative limitations.2 Many cancers, such as lung cancers3 and glioblastoma,4 upregulate the expression of the telomerase holoenzyme to repair degraded telomeres and bypass these limitations, allowing them to proliferate indefinitely. Recently, the DBHS family of proteins have been implicated in the assembly of the active telomerase core complex. In this poster presentation, we report our investigations towards peptide-based inhibitors against the DBHS family of proteins. We identified a candidate 16-mer partially helical peptide, P01, by screening peptide fragments from the dimerisation domain of NONO, a member of the DBHS family. Subsequently, a double cysteine mutant for P01 was designed for stapling, and a series of side-chain cyclisation linkers were tested to determine the effect of the linker moiety on binding. Interestingly, an increase in binding was observed upon mutating two residues into cysteines, while cyclisation with many of the helix-matching linkers resulted in loss of binding. In addition, we also report the results of alternative screens against NONO, including fragment screening and various display approaches to cyclic peptide screening.5-6

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