Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes

Abstract

Cyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also their passive membrane permeability. As the “journey” through membranes cannot be monitored experimentally, little is known about the underlying process, which hinders rational design. Here, we use molecular simulations to uncover how cyclic peptides permeate a membrane. We show that side chains can act as “molecular anchors”, establishing the first contact with the membrane and enabling insertion. Once inside, the peptides are positioned between headgroups and lipid tailsa unique polar/apolar interface. Only one of two distinct orientations at this interface allows for the formation of the permeable “closed” conformation. In the closed conformation, the peptide crosses to the lower leaflet via another “anchoring” and flipping mechanism. Our findings provide atomistic insights into the permeation process of flexible cyclic peptides and reveal design considerations for each step of the process.

Chamelogk: A Chromatographic Chameleonicity Quantifier to Design Orally Bioavailable Beyond-Rule-of-5 Drugs

“…For instance, kinetic and thermodynamic solubilities are not often correlated, and the role played by active transport in permeability processes is poorly understood. , Moreover, for most PROTACs, both solubility and permeability experiments can be affected by the sticky properties of the compounds. Therefore, the use of ad hoc chromatographic descriptors to provide a first screening of the solubility/permeability profile of drug candidates and thus reduce the number of solubility and permeability measurements could improve the efficiency of the drug discovery bRo5 pipeline. ,,, To highlight the relevance of this strategy, we recently used BRlogD and log k w IAM (lipophilicity) to classify the solubility of 15 unrelated PROTACs and Δ log k W IAM (polarity) to model cellular passive permeability for a reduced set of PROTACs. Moreover, another polarity descriptor, EPSA, is widely implemented in drug discovery to classify cell permeability of cyclic peptides .…”

“…In fact, some studies highlight the need to display congruent conformations (equivalent conformations in polar and nonpolar media) to lower the price that closed conformations should pay when passing from nonpolar to polar environments . Additional studies were published to further inspect macrocycle chameleonicity. − For instance, Rossi Sebastiano and co-workers used a data set of crystallographic drug structures to highlight that dynamic IMHBs (dIMHBs) and hydrophobic collapse are two structural chameleonicity drivers . Besides macrocycles, chameleonicity may also affect other bRo5 classes such as nonmacrocyclic compounds and PROTACs (often referred to as degraders), defined as heterobifunctional molecules composed of three parts: a warhead targeting a protein of interest (POI), an E3 ligand recruiting an E3 ligase enzyme, and a linker connecting both regions .…”

Conformations of Macrocyclic Peptides Sampled by Nuclear Magnetic Resonance: Models for Cell-Permeability

“…These findings suggest that the transition to the hydrophobic conformation involves the formation of H-bonds, initiated by the formation of a type VIa β-turn in the intermediate state prior to entering the membrane. The indole side chain may serve as an anchor for membrane insertion . Within the lipophilic membrane, H-bond formation between Trp 1 H and Iml 11 O reduces the exposure of polar groups by the formation of a γ-turn.…”

“…In polar solvents, OmphA adopts an "open" conformation characterized The indole side chain may serve as an anchor for membrane insertion. 80 Within the lipophilic membrane, H-bond formation between Trp 1 H and Iml 11 O reduces the exposure of polar groups by the formation of a γ-turn. Furthermore, the indole side chain of Trp 1 is positioned toward Sar 12, resembling the "indole-in" state.…”

Stabilized cyclic peptides as modulators of protein–protein interactions: promising strategies and biological evaluation

“…For example, molecular simulations have been applied to investigate the membrane translocation process of cyclic peptides. 129 In addition, common structural features of cell permeable and membrane impermeable cyclic peptides have been examined and summarized. 130 These studies will provide useful insights to understand the molecular mechanism of cell penetration and offer empirical evidence to rationally design cell-permeable and biologically active cyclic peptides.…”