Macrocyclic α-Helical Peptide Drug Discovery

Abstract

Macrocyclic α-helical peptides have emerged as a promising new drug class and within the scope of hydrocarbon-stapled peptides such molecules have advanced into the clinic. The overarching concept of designing proteomimetics of an α-helical ‘ligand’ which binds its cognate ‘target’ relative to α-helical interfacing protein-protein interactions has been well-validated and expanded through numerous investigations for a plethora of therapeutic targets oftentimes referred to as “undruggable” with respect to other modalities (e.g., small-molecule or proteins). This chapter highlights the evolution of macrocyclic α-helical peptides in terms of target space, biophysical and computational chemistry, structural diversity and synthesis, drug design and chemical biology. It is noteworthy that hydrocarbon-stapled peptides have successfully risen to the summit of such drug discovery campaigns.

Development and Regulatory Challenges for Peptide Therapeutics

“…Importantly, it is well-recognized nowadays that peptides are a compelling modality for both “classic” targets as well as “undruggable” targets versus small molecules that may have inability to bind to large, flat binding surfaces or antibodies that have limited cell permeability to access intracellular targets. 19 -27…”

“…In terms of recently FDA-approved peptide drugs (Figure 2), such target space is well exemplified across many therapeutic indications, including endocrine, gastrointestinal, and infectious diseases as well as cancer. Interestingly, there is a significant effort focused on macrocyclic peptides and peptidomimetics 19 -27 that are being advanced, and unquestionably these will further increase relative to the third wave of peptide drug discovery to build upon what has already been accomplished. Yet, a remaining challenge for peptide therapeutics is drug delivery.…”

“…Therefore, peptides, and more precisely, macrocyclic peptides have become highly favored within the molecular armamentarium of biotech/pharma to become a new therapeutic modality to tackle intracellular target space in innovative ways. 19 -27 Some noteworthy examples include cyclosporine-A (CsA), 29 cyclic CPPs, 30 and ATSP-7041 31 (Figure 3).…”

“…22,30,33 Such cyclic CPPs may be used as carriers or be designed to incorporate a peptide pharmacophore for an intracellular therapeutic target. Stapled α−helical peptides have also arisen as a promising new class of macrocyclic peptides 24,26,34 -36 and have recently advanced into the clinic (ie, ALRN-6924). 37 ATSP-7041 31,38 -40 (a progenitor of ALRN-6924) is a benchmark stapled α−helical peptide to explore cellular permeability that seems to fit into a third mechanism which has been dubbed lipophilic partitioning that is different from the passive transport properties of CsA and the cationic partitioning (and endosomal pathway) of cyclic CPPs.…”

Photochemical Methods for Peptide Macrocyclisation

“…To overcome these limitations, the design and synthesis of macrocyclic PSPs has become increasingly prominent [1–4, 8, 10] . Macrocyclisation (defined as cyclisation to form rings of ≥12 atoms) can occur through head‐to‐tail, head‐to‐sidechain, sidechain‐to‐tail or sidechain‐to‐sidechain coupling (stapling) (Figure 1), delivering cyclical products, which possess a number of advantageous characteristics over their linear counterparts: [11] i) structures are rigidified, stabilising or enforcing peptide conformations that mimic elements of protein secondary structure [12] , α‐helices, [13–20] β‐sheets [21] and β‐hairpin turns [22] , which would otherwise be unstable can all be induced by cyclisation; ii) cyclised peptides exhibit increased stability to proteolysis, thus prolonging their biological activity and improving their pharmacokinetics. This stability can result from a number of factors, including the poor fit of macrocycles into the active sites of endopeptidases, [23] resistance to the activity of exoproteases that preferentially cleave near the peptide N‐ or C‐termini, [11] or the formation of α‐helices that are resistant to proteolysis due to the presence of a rigidifying, intramolecular, hydrogen‐bonding network; [17] iii) binding efficiency for a target is often improved, an effect classically attributed to cyclic structures being held in conformations better disposed towards binding, with a resultant reduction in the entropic penalty to binding [23, 24] .…”