In our previous posts (Part I and Part II), we explored the rising interest in linear peptides and macrocycles as beyond-Rule-of-5 modalities reshaping the landscape of medicinal chemistry.

We also highlighted the crucial role of traditional and non-traditional dipeptide mimics in advancing lead- and drug-like molecules with reduced peptide character.

In this post, we focus on macrocycles.

Macrocycles are an established yet innovative modality that bridges the gap between classical Ro5-compliant small molecules and biologics (Fig. 1). While many macrocycle leads reside at the lower molecular weight spectrum within the beyond Ro5 space, they feature exceptional molecular complexity and unique functional opportunities.

“Macrocycles” is a broad term encompassing diverse chemotypes, including peptidic, semi-peptidic and non-peptidic structures, with a wide range of applications.

At SpiroChem, we are agonistic in selecting specific types of macrocycles, and selected examples are highlighted in Fig. 2. Beyond our proprietary SpiroQuest library of semi-peptidic macrocycles, we have successfully delivered client projects leveraging an extensive variety of macrocycles built on different cyclization topologies (Fig. 2).

Our synthetic toolbox goes far beyond commonly used amide and disulfide cyclizations.

We have developed a versatile, solid-phase compatible platform for modular coupling reactions for main chain elongation and macrocyclization chemistries tailored to complex project needs.

The main types of chemistries routinely used at SpiroChem are shown in Fig. 3. Moreover, conjugation strategies using macrocycles as functional entities have emerged as a key focus area at SpiroChem.

This requires specialized expertise in linker design and attachment methodologies.

We are pioneering applications where macrocycles serve as antibody payloads, radionuclide homing devices, PROTAC targeting moieties and chemical biology tools, for example for assay development.

Representative macrocyclic conjugates are shown in Fig. 4. At SpiroChem, we support your macrocycle projects through every stage, from initial hit generation and validation through multiparameter optimization to the construction of sophisticated conjugates.

Our hierarchical approach combines cutting-edge molecular design, modern synthetic chemistry and deep solid-phase peptide chemistry expertise, enabling us to deliver on the most ambitious goals.