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The field of medicinal chemistry is witnessing growing interest in peptides, peptidic, and semi-peptidic macrocyles as promising beyond rule-of-5 (bRo5) therapeutic modalities. These complex structures are proving effective in modulating targets that were previously considered "undruggable“.
However, both linear and cyclic peptides present several limitations that hinder their broader therapeutic development. These challenges include rapid metabolic degradation, fast clearance from the body, high conformational flexibility, resulting in reduced target specificity and the potential for immunogenicity.
To effectively evolve peptides into drug-like candidates, medicinal chemists need robust tools that support the systematic de-peptidization of lead compounds.
Identifying high-quality hits is the foundation of a successful peptide discovery program. Whether starting from hits generated by DEL, phage display, or mRNA display, from dedicated screening campaigns, or from the SpiroChem Macrocycle Library , the quality of the initial hit set is critical to the success of downstream SAR and optimization.
By combining diverse peptide and macrocyclic chemical space with robust screening, hit validation, and smart library design, we help identify potent, selective, and developable starting points for challenging drug discovery programs.
Recently, SpiroChem and PeptiFinder Biotech announced a strategic partnership, establishing an integrated discovery engine that combines advanced hit generation through mRNA display with proprietary synthetic platforms and medicinal chemistry expertise, creating a highly complementary and differentiated offering for early discovery.
To effectively evolve peptides into drug-like candidates, medicinal chemists need robust tools that support the systematic de-peptidization of lead compounds by stabilizing bioactive conformations, enhancing potency and selectivity, improving metabolic resistance, optimizing physicochemical and pharmacokinetic profiles.
To tackle these challenges, SpiroChem has developed and applied diverse synthetic strategies to access diverse unnatural amino acid families in which metabolic hotspots are hindered or substituted. These complex building blocks can be modularly incorporated into lead peptides to overcome specific structural and pharmacological liabilities.
Amino acid surrogate examples to address:
Peptide and macrocycle drug discovery requires not only innovative hit-identification technologies, but also sophisticated synthetic chemistry and a deep understanding of molecular conformation to drive effective lead optimization. Conformational principles govern peptide and macrocycle recognition of therapeutic targets.
Peptidomimetic strategies can be used to eliminate pharmacological liabilities while preserving the structural features essential for activity. Our toolbox contains secondary-structure mimetics, with for example the ability to stabilize reverse turns and extended strand conformations while maintaining true conformational compatibility with the parent peptide.
