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Cyclization restricts the conformational flexibility of a peptide to a subset of structures sampled by the linear form and can effectively pre-organize a larger compound for target binding. As a result of this pre-organization, the entropic penalty for target binding is decreased and in some cases cyclization can lead to an increase in target affinity and specificity. The cyclic nature of this kind of peptide enhances their stability against proteolytic degradation by peptidases.

Our team has a wide expertise in various cyclization chemistries (e.g., ring closing metathesis, lactamization, click chemistry, disulphide bridges formation, reductive amination) and with this diversity we can take advantage of our large in-house collection and ad-hoc synthesis of novel amino acids.

Peptide Discovery - Macrocyclic drugs: Synthesis of NonNatural Amino Acids
Peptide Discovery - Macrocyclic drugs: Synthesis of NonNatural Amino Acids

The search for innovative ways to bind and modulate challenging biological targets, which can modify diseases, is providing a strong drive for chemists to explore new areas of chemical space. In the past few years there has been an increased interest in exploring larger (700–1900 Da) macrocyclic compounds as a new modality to address undruggable biological targets such as protein–protein interactions (PPIs), especially intracellular ones and growth factor receptors. Macrocycles have proven to be very valuable tools in the chemical space beyond the conventional drug-like small molecules and the biological drugs such as monoclonal antibodies.

IRBM’s Peptide Chemistry group has acquired a broad knowledge in macrocyclic peptides synthesis across different therapeutic areas. Both solution and solid phase-synthesis approaches, together with the introduction of novel amino acids, are routinely applied to deliver complex molecules containing multiple constraints. Strong synthetic capabilities in the team include ad hoc preparations of multi-functionalized building blocks and linkers, cyclization chemistries and chemo-selective conjugations.

Peptide Discovery – Macrocyclic Drugs: Synthesis of Building Blocks for Linkers
Peptide Discovery – Macrocyclic Drugs: Synthesis of Building Blocks for Linkers

Tools and strategies are in place for producing potent and high-affinity bioavailable hits with improved chemical and metabolic stability and an optimized pharmacological profile through multi-parameters modifications of labile spots.

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