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Our chemists are equipped to explore new chemical spaces to find innovative ways to bind and modulate challenging biological targets. Macrocyclic peptides offer an exciting new modality to address therapeutic targets such as protein–protein interactions (PPIs) and complex membrane receptor systems.

The IRBM team has broad expertise in macrocycle chemistry across different therapeutic areas helping to extend the drug-hunter’s toolkit beyond conventional drug-like small molecules and biological drugs such as monoclonal antibodies.

Cyclization restricts the conformational flexibility of a peptide to a subset of structures sampled by the linear form, effectively pre-organizing it for target binding. Decreasing the entropic penalty in this way leads to improved affinity, selectivity and stability.

We use both solution and solid-phase approaches to optimize macrocyclic leads from various display technology libraries such as mRNA and display libraries.

infographic showing protein-protein interactions leading to cyclic peptide leads

This strategy has proven successful in many projects and the IRBM team has made significant contributions to the field, including with the development of MK-0616 an oral potent tricyclic PCSK9 peptide inhibitor in collaboration with the drug discovery team at Merck & co.

At IRBM, we routinely perform state-of-the-art cyclization chemistries including ring closing metathesis, lactamization, click chemistry, disulphide bridges formation and reductive amination. Our extensive in-house collection of non-natural amino acids combined with our unparalleled expertise in the ad-hoc synthesis of building blocks using solution chemistry, enables us to design the widest array of side-chain modifications and multifunctional linkers for macrocyclizations.

Graphic depicting The Peptide Drug Discovery Process

These strategies, combined with late-stage functionalization of pre-assembled macrocycles and chemo-selective conjugations, can be exploited for multi-parameter modifications to address labile spots. Our lead optimization processes have generated many preclinical candidates, several of which have successfully entered the clinic.

In the past few years, there has been an increased interest in exploring larger (700–2000 Da) macrocyclic compounds as a new modality to address undruggable biological targets such as protein–protein interactions (PPIs).

Elisabetta Bianchi, Senior Director, Peptide Chemistry, IRBM

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