Introduction
Cyclic peptide natural products and their synthetic mimics have gained prominence as potential sources of next‐generation therapeutics and biological probes [1–4]. The size and structural complexity of these compounds sets them apart from common synthetic drugs, allowing them to access the “undruggable” target space beyond enzymatic active sites and receptor binding pockets to include activities against a variety of nontraditional targets [4]. Although cyclic peptides have molecular weights and polar group counts that exceed the typical parameters for “drug‐likeness” [5, 6], many are capable of penetrating cells by passive diffusion, and some, such as cyclosporin A, are orally bioavailable [7]. Passive diffusion offers an advantage over other forms of permeation such as paracellular transport, carrier‐mediated transport, and active non‐receptor‐mediated uptake (e.g., micropinocytosis) because the ability to cross the membrane is dictated by the intrinsic properties of the molecule (e.g., molecular weight, number of intramolecular hydrogen bonds (IMHBs), polar surface area, flexibility, lipophilicity) rather than those of the target tissue or cellular physiology (e.g., size of tight junctions, type of transport proteins, invagination of the membrane in response to surface assemblies). Thus, these natural products may provide insights into the requirements for optimizing the ADME properties of large macrocycles.
Further, the stereochemical and conformational complexity of cyclic peptides serves as a model for the design of synthetic scaffolds capable of modulating challenging biological targets such as protein–protein interactions and allosteric binding sites in both extracellular and intracellular space [8–13]. Despite this potential, few efforts have been made to systematically assess the relationship between the structure, pharmacokinetics, and bioactivity of cyclic peptide natural products. This is due in part to the limited number of known passively permeable cyclic peptide and cyclic peptide/polyketide natural products. Therefore the generality of cyclic peptides as orally bioavailable bioactive scaffolds remains an open question.
The few studies that have systematically explored the relationships between structure and permeability in cyclic peptides have been limited to a small subset of methylated (1) [14] and non‐methylated (2) [15] cyclic hexapeptide scaffolds that bear resemblance to baceridin (3) [16], segelin I (4) [17], and the nocardiamide (5/6) [18] cyclic hexapeptide natural products (Figure 5.1 and Chapter 3) [19–22].
The work of Lokey and Jacobson [23–27], Fairlie and Craik [28–30], and others has begun to elucidate the structure– permeability relationships of more complex natural products, but the vast majority of these studies have been limited to cyclic penta‐ and hexapeptides with no observed bioactivity. Thus, the new frontier in understanding structure–permeability relationships in cyclic peptides has moved to the chemical space that encompasses macrocycles of higher molecular weight [31, 32], greater structural complexity, and significant bioactivity.
Here, we first discuss the two‐dimensional and three dimensional (3D) structures of known passively permeable cyclic peptide natural products and then highlight recently discovered cyclic peptide natural products with notable bioactivity that could serve as starting structures for future systematic structural studies to optimize oral absorption.
October 2017
Wiley Publishers
Read online book
by Markus Boehm, Kevin Beaumont, Rhys M Jones, Amit S. Kalgutkar, Liying Zhang, Karen Atkinson, Guoyun Bai, Janice A. Brown, Heather Eng, Gilles H. Goetz, Brian R Holder, Bhagyashree Khunte, Sarah Lazzaro, Chris Limberakis, Sangwoo Ryu, Michael J Shapiro, Laurie Tylaska, Jiangli Yan, Rushia Turner, Siegfried S. F. Leung, Mahesh Ramaseshan, David A. Price, Spiros Liras, Matthew P Jacobson, David J. Earp, R. Scott Lokey, Alan M Mathiowetz, and Elnaz Menhaji-Klotz
Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators.
ABSTRACT: The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side chain diversity well beyond that of natural amino acids. At the same time, computational calculations and experimental assays were used to track and reduce polarity while closely monitoring physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 x 10-6 cm/sec). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
October 18, 2017
Journal of Medicinal Chemistry
Read online article
by Matthew R. Naylor, Andrew T. Bockus, Maria-Jesus Blanco, Scott Lokey
Highlights
As interest in protein–protein interactions and other previously-undruggable targets increases, medicinal chemists are returning to natural products for design inspiration toward molecules that transcend the paradigm of small molecule drugs. These compounds, especially peptides, often have poor ADME properties and thus require a more nuanced understanding of structure-property relationships to achieve desirable oral bioavailability. Although there have been few clinical successes in this chemical space to date, recent work has identified opportunities to introduce favorable physicochemical properties to peptidic macrocycles that maintain activity and oral bioavailability.
May 29, 2017
Elsevier
Read online article
by Cameron R. Pye, William M. Hewitt, Joshua Schwochert, Terra D. Haddad, Chad E. Townsend, Lyns Etienne, Yongtong Lao, Chris Limberakis, Akihiro Furukawa, Alan M. Mathiowetz, David A. Price, Spiros Liras, and R. Scott Lokey
Macrocyclic peptides are considered large enough to inhibit “undruggable” targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation…
January 6, 2017
Journal of Medicinal Chemistry
Read online article
by Akihiro Furukawa, Chad E. Townsend, Joshua Schwochert, Cameron R. Pye, Maria A. Bednarek, and R. Scott Lokey
Synthetic and natural cyclic peptides provide a testing ground for studying membrane permeability in nontraditional drug scaffolds. Cyclic peptomers, which incorporate peptide and N-alkylglycine (peptoid) residues, combine the stereochemical and geometric complexity of peptides with the functional group diversity accessible to peptoids. We synthesized cyclic peptomer libraries by split-pool techniques, separately permuting side chain and backbone geometry, and analyzed their membrane permeabilities using the parallel artificial membrane permeability assay. Nearly half of the side chain permutations had permeability coefficients (Papp) > 1 × 10–6 cm/s. Some backbone geometries enhanced permeability due to their ability to form more stable intramolecular hydrogen bond networks compared with other scaffolds. These observations suggest that hexameric cyclic peptomers can have good passive permeability even in the context of extensive side chain and backbone variation, and that high permeability can generally be achieved within a relatively wide lipophilicity range.
October 3, 2016
Journal of Medicinal Chemistry
Read online article
by Joshua Schwochert, Yongtong Lao, Cameron R. Pye, Matthew R. Naylor, Prashant V. Desai, Isabel C. Gonzalez Valcarcel, Jaclyn A. Barrett, Geri Sawada, Maria-Jesus Blanco, and R. Scott Lokey
Cyclic peptide (CP) natural products provide useful model systems for mapping “beyond-Rule-of-5” (bRo5) space. We identified the phepropeptins as natural product CPs with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural CPs whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.
June 6, 2016
ACS Medicinal Chemistry Letter
Read online article
by Leung SS, Sindhikara D, Jacobson MP
We investigate the relationship between passive permeability and molecular size, in the context of solubility-diffusion theory, using a diverse compound set with molecular weights ranging from 151 to 828, which have all been characterized in a consistent manner using the RRCK cell monolayer assay. Computationally, each compound was subjected to extensive conformational search and physics-based permeability prediction, and multiple linear regression analyses were subsequently performed to determine, empirically, the relative contributions of hydrophobicity and molecular size to passive permeation in the RRCK assay. Additional analyses of Log D and PAMPA data suggest that these measurements are not size selective, a possible reason for their sometimes weak correlation with cell-based permeability.
May 23, 2016
Journal of Chemical Information and Modeling
Read online article
by Andrew T. Bockus, Joshua A. Schwochert, Cameron R. Pye, Chad E. Townsend, Vong Sok, Maria A. Bednarek, and R. Scott Lokey
It is well established that intramolecular hydrogen bonding and N-methylation play important roles in the passive permeability of cyclic peptides, but other structural features have been explored less intensively. Recent studies on the oral bioavailability of the cyclic heptapeptide sanguinamide A have raised the question of whether steric occlusion of polar groups via β-branching is an effective, yet untapped, tool in cyclic peptide permeability optimization. We report the structures of 17 sanguinamide A analogues designed to test the relative contributions of β-branching, N-methylation, and side chain size to passive membrane permeability and aqueous solubility. We demonstrate that β-branching has little effect on permeability compared to the effects of aliphatic carbon count and N-methylation of exposed NH groups. We highlight a new N-methylated analogue of sanguinamide A with a Leu substitution at position 2 that exhibits solvent-dependent flexibility and improved permeability over that of the natural product.
August 26, 2015
Journal of Medicinal Chemistry
Read online article
by Christopher L Ahlbach, Katrina W Lexa, Andrew T Bockus, Valerie Chen, Phillip Crews, Matthew P Jacobson & R Scott Lokey
Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane permeabilities of 39 cyclic peptide natural products, and interpret the results using a computational permeability prediction algorithm based on their known or calculated 3D conformations. We found that the permeabilities of these compounds, measured in a parallel artificial membrane permeability assay, spanned a wide range and demonstrated the important influence of conformation on membrane permeability. These results will aid in the development of these compounds as a viable drug paradigm.
June 12, 2015
Future Science
Read online article
This site is intended for US residents only.
© 2024 Circle Pharma. All Rights Reserved.
