Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity

Abstract

Large macrocyclic peptides can achieve surprisingly high membrane permeability,a lthough the properties that govern permeability in this chemical space are only beginning to come into focus.W eg enerated two libraries of cyclic decapeptides with stable cross-b conformations,and found that peptoid substitutions within the b-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing b-strands led to "chameleonic" species that were rigid in nonpolar media but highly flexible in water.B oth rigid and chameleonic compounds showed high permeability over aw ide lipophilicity range,w ith peak permeabilities differing significantly depending on scaffold rigidity.Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides,and that scaffold rigidity can be used to tune optimal lipophilicity.

Interplay among Conformation, Intramolecular Hydrogen Bonds, and Chameleonicity in the Membrane Permeability and Cyclophilin A Binding of Macrocyclic Peptide Cyclosporin O Derivatives

“…Hence, various molecular scaffolds in this chemical space have been systematically investigated to measure the degree of impact of flexibility and rigidity on membrane permeability. 23,37,39,76 CsA has attracted interest in biological applications for decades and has recently been reinvestigated as a representative chameleonic macrocycle. 35 In general, CsA derivatives show high membrane permeability, but it is reduced when polarity is increased or chameleonic behavior is lost.…”

“…A recent report by Lokey and co-workers indicated that both rigid and chameleonic macrocyclic peptides (i.e., libraries A and B, respectively) showed high membrane permeability. 23 Other rigid macrocycles, such as rifampicin 76 and cyclic hexapeptides 39 also demonstrated membrane permeability and oral bioavailability. An in vivo PK evaluation of CsO, a macrocycle that is more rigid than CsA, exhibited an approximately 2-or 3-fold decrease in oral bioavailability (F = 12 ± 0.3%), while the PAMPA permeability decrease was 7fold compared to CsA.…”

“…However, it is now accepted that favorable conformational features that permit membrane permeation are intramolecular hydrogen bonds and a reduced SASA, which are obtained by masking amide protons (e.g., β-turns and β-sheets) in a low dielectric medium. 13,19,22,23,27,33,34 Recently, some macrocyclic compounds with high membrane permeability have been shown to exhibit conformational changes depending on the environmental polarity. 19,35,36 These chameleonic macrocycles favor an "open" conformation in aqueous environments by exposing polar groups toward the exterior to interact with water molecules and increase aqueous solubility, while a "closed" conformation is predominantly adopted in hydrophobic environments to shield the polar backbone with intramolecular hydrogen bonds or lipophilic side chains, leading to improved membrane permeability.…”

Cyclosporin Structure and Permeability: From A to Z and Beyond

“…Instead, these more flexible analogues had decreased or similar membrane permeabilities compared to CsA. At least for this small sample set of cyclosporins, with the assumption that changing the lipophilicity has no effect on the permeability, 105 this suggests that some degree of structural integrity is necessary for optimal cyclosporin membrane permeability. Models that take into account this structure−permeability relationship are needed.…”

“…Many studies have proposed that the conformational flexibility of cyclosporins may be one factor that aids permeability through membranes, 37,66,75 although recent work suggests a more complicated, interdependent relationship among peptide flexibility, lipophilicity, and membrane permeability. 105 May increased the flexibility of CsA by substituting sarcosine (N-methylglycine, MeGly) into residues 4 and 6 of CsA, respectively. 103 Sarcosine is able to sample significantly more regions of ϕ/ψ backbone dihedral space compared with non-Gly amino acids.…”