Call for Papers: Macrocycles as Therapeutic Modalities for Challenging Drug Targets

The perception of what constitutes a viable therapeutic agent has expanded considerably, moving beyond traditional small molecules to embrace more complex architectures. Among these, macrocyclic compounds have emerged as a promising class due to their unique ability to modulate challenging biological targets. Unlike conventional small molecules, macrocycles possess intermediate molecular weights, conformational restraint, and extended surface areas that enable high-affinity binding to flat protein surfaces and protein–protein interaction interfaces─targets often deemed “undruggable”. Notably, among human disease-related target proteins, up to 85% are still considered undruggable. (1) Macrocycles offer a compelling combination of adaptability, selectivity, and improved pharmacological profiles. (2) Their cyclic structures reduce conformational entropy upon binding, enhancing target engagement and increasing binding affinity. These characteristics make them particularly valuable for interfering with intricate biomolecular interactions that are central to disease mechanisms but remain elusive to typical small molecules or biologics (Figure 1). Recent years have witnessed significant advances in synthetic strategies, computational design, and biological evaluation of macrocyclic compounds. Hiroaki Suga, (3) Christian Heinis, (4) Herbert Waldmann, (5) Felix Hausch, (6) Jan Kihlberg, (7) Mate Erdelyi, (2) Ke Ding, (8) Honglin Li, (9) Xiaoyun Lu, (10) we (11) and others have contributed to advancing research on the medicinal chemistry of macrocycles. Notably, macrocycles have shown promise in targeting oncogenic proteins such as KRAS, transcription factors, and various regulatory complexes through innovative mechanisms, including molecular glue strategies that induce neomorphic interactions. Furthermore, the integration of macrocyclic scaffolds with peptide, (3,11) peptidomimetic, or synthetic chemistries has broadened the horizon for developing compounds with enhanced stability, membrane permeability, and oral bioavailability. Despite these advances, the development of macrocyclic therapeutics continues to face considerable challenges. Limitations in synthetic accessibility, structural diversification, and predictive modeling hinder the efficient exploration of chemical space. There is a pressing need for novel macrocyclization methodologies, efficient screening platforms, and strategies to optimize the drug-like properties of macrocyclic compounds. This Special Issue of the Journal of Medicinal Chemistry, dedicated to “Macrocycles as Therapeutic Modalities for Challenging Drug Targets”, invites contributions that highlight recent innovations in the design, synthesis, and application of macrocycles as therapeutic agents. Topics of interest include, but are not limited to Novel macrocyclization reactions and strategies Computational design and modeling of macrocyclic compounds Macrocyclic peptides and peptidomimetics Targeted protein degradation and molecular glues involving macrocycles Macrocyclic inhibitors of protein–protein interactions Strategies to improve cell permeability and oral bioavailability Case studies targeting undruggable proteins (e.g., RAS, c-MYC, transcription factors) Advances in screening technologies for macrocyclic libraries Structural studies and mechanistic insights into macrocycle-target interactions The submission deadline for the Special Issue is May 31, 2026. Articles will be published on a rolling basis in regular issues upon acceptance and later assembled in a dedicated online collection. The Journal of Medicinal Chemistry welcomes original research Articles, Perspectives, and Drug Annotations. We look forward to receiving your submissions by the deadline. Please consult the Author Guidelines before submission of the manuscript. For any questions regarding submission into this Special Issue, they may be sent to jmc@jmedchem.acs.org. This article references 11 other publications. This document has been updated Click for further information. This article has not yet been cited by other publications.