Macrocyclic peptides and peptidomimetics (MPPs) have emerged as a powerful therapeutic class in peptide-based drug discovery, uniquely positioned to modulate challenging protein-protein interactions (PPIs). While dysregulated PPIs drive diverse human pathologies, including cancer, metabolic disorders, neurodegenerative proteinopathies, inflammatory conditions, and microbial infections, targeting them remains difficult. Traditional small molecules lack the surface area to bind large, flat PPI interfaces, whereas linear peptides suffer from rapid proteolytic degradation and poor cell permeability. MPPs overcome these limitations by bridging the gap between small molecules and biologics. Their cyclic architecture provides conformational rigidity minimizing entropic penalties and maximizing binding affinity and selectivity. This structural pre-organization also enhances metabolic robustness, protease resistance, and cellular permeability. This review comprehensively examines the biological significance of PPIs in human disease and details how MPPs effectively modulate historically undruggable targets. We highlight current synthetic strategies, peptide engineering platforms, and the clinical and preclinical status of leading MPP candidates, while weighing their operational advantages and limitations. Finally, we analyze the contemporary market trajectory and emerging commercial opportunities, positioning MPPs as next-generation, PPI-targeting therapeutics.
Alzheimer's disease (AD) remains a formidable global health challenge, driving the urgent need for potent and selective therapeutics targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme involved in the generation of amyloid-β (Aβ) peptide and a promising target for disease-modifying interventions. In this work, approximately 16 million small molecules from diverse databases were subjected to ligand-based virtual screening (LBVS), using LY3202626 as a reference compound, to identify new potent inhibitors of BACE1. LY3202626 is a highly potent, central nervous system (CNS) penetrant BACE1 inhibitor (IC50 = 0.615 nM) that has progressed to clinical trials, demonstrating efficacy at low doses against BACE1 activity. The lead candidates identified using ensemble molecular docking displayed stronger binding affinities (-11.2 to -9.6 kcal mol-1) to BACE1 as compared to LY3202626. Notably, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis revealed high-affinity binding of ChEMBL3667410 (C1), ChEMBL3667414 (C2), and ChEMBL3976114 (C5) with binding affinities of -32.9 ± 0.8, -33.6 ± 1.8, and -36.1 ± 1.7 kcal mol-1, respectively, to BACE1 as compared to LY3202626 (-29.9 ± 1.8 kcal mol-1). Furthermore, MD simulations demonstrated enhanced structural stability and reduced residual fluctuations in BACE1 on the incorporation of C1, C2, and C5, as compared to apo-BACE1 and BACE1-LY3202626. Interestingly, the conformational snapshots, flap distances, and free energy landscape (FEL) analyses highlighted a closed flap, Val67-Glu77 (non-active) conformation in BACE1-C5 in comparison to an open flap (active) conformation in apo-BACE1, and partial restriction in the access to the active site of BACE1 due to the flap movement noticed in the presence of LY3202626, C1, and C2. Notably, conformational microstate analysis revealed key hydrogen bond interactions of C5 with the 10s loop (Gly11, Gly13), flap residues (Trp76), the catalytic residue (Asp228), Gly230, and Thr231 of BACE1, depicting its high-affinity binding to key residues of BACE1 and its potential as an effective inhibitor of BACE1 activity. The comprehensive in silico methodology in this work illuminated the inhibitory mechanism of LY3202626 and top hit compounds against BACE1 activity for the first time, which, in turn, will be highly valuable in further optimization and structural refinement using various functional group modifications to yield more potent next-generation therapeutic candidates against BACE1 in AD.
