Designing Diketopiperazines to Disrupt TRBD-TERC Binding in Telomerase

Overview

Telomerase is a ribonucleoprotein reverse transcriptase that preserves chromosomal integrity by extending telomeres, yet it is upregulated in over 85% of cancers, enabling indefinite replication. Current inhibitors such as Imetelstat target the telomerase RNA component (TERC) but face limitations including instability, delivery challenges, and off-target effects. This project investigates an alternative strategy: using small molecule cyclic diketopiperazines (DKPs), a class of peptidomimetics known for stability and diverse side-chain (R-group) functionalities. Due to these properties, DKPs can disrupt essential steps in telomerase assembly, such as TRBD-TERC binding. To evaluate their efficacy, DKPs were computationally docked to the crystal structure of the TRBD domain of TERT and the CR4/5 region of telomerase RNA from Oryzias latipes using UCSF Chimera and AutoDock Vina. Given the high density of positively charged arginine residues within the TRBD binding interface, negatively charged R groups were prioritized to promote electrostatic complementarity. Aromatic residues such as tyrosine, phenylalanine, and tryptophan were incorporated to assess potential π–π stacking and hydrophobic interactions with the RNA backbone. Docking simulations demonstrated that DKPs containing both negatively charged and aromatic R groups exhibited the strongest predicted binding affinities and most favorable binding conformations. These findings support the feasibility of targeting the TRBD–TERC interface using cyclic peptidomimetics and provide a rational foundation for subsequent in vitro validation as a potentially more precise anticancer strategy.

Competition history

• CSEF 2026 Biochemistry/ Molecular Biology (Senior Division) · Entry S-04-06

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