Macrocyclic peptides as the next-generation immuno-oncology therapeutics


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Challenge: When considering drug discovery, the pharmaceutical industry faces many challenges. Indeed, each drug class, namely small molecules, antibodies or peptides-based therapeutics, possesses its own characteristics and comes with its own challenges. While presenting similar features than peptides in terms of activity, selectivity and potency, macrocycle peptides also present enhanced permeability and stability towards proteases. Macrocycles are also ideally positioned to target intracellular protein-protein interactions, which have long been considered undruggable. Because of those features, they have attracted increased attention from the pharmaceutical industry.

Solution: The team recently developed genetically encoded bicyclic libraries (BiGEL2) to produce macrocycles exhibiting unprecedented stability in conditions reminiscent of an aggressive proteolytic environment of the gastrointestinal tract to allow for oral availability and membrane permeability to reach intracellular targets. In this project, and as proof of concept for their BiGEL2 discovery pipeline, the team will target glycobinding proteins, known to be targets of high complexity in drug development. The team will identify bicyclic inhibitors for the immune-oncology targets Siglec 7 and 9, recently reported to be implicated in cancer tumors’ avoidance of immune cells. They will validate the performance of these inhibitors in vitro, in cell lines ex vivo and in mouse models in vivo. They will also evaluate membrane permeability, bio- and oral availability and distribution of a diverse collection of bicyclic structures. As part of this proposal, they will offer selection of bicyclic scaffolds for two targets provided by each CQDM partnering pharmaceutical company.

Expected achievements/Impact : By the end of the project, the team will have expanded the range of the targets accessible to their technology, focusing their efforts on difficult-to-explore targets. This project will add value to the BiGEL2 pipeline by demonstrating its capacity to fuel IND-enabling studies for immuno-oncology targets that have no known small molecule inhibitors to date. By doing so, 48Hour Discovery strives to accelerate drug discovery and attract new pharmaceutical ventures that aim to develop drugs for new molecular targets.

Principal Investigator:
Ratmir Derda
48Hour Discovery
Matthew Macauley 
University of Alberta
Ongoing Project
$ 800,000 / 2 years
Supported by CQDM through:
– Merck Canada
And by co-funding partners
– Glyconet
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