by Joshua Schwochert, Rushia Turner, Melissa Thang, Ray F Berkeley, Alexandra R Ponkey, Kelsie M. Rodriguez, Siegfried S F Leung, Bhagyashree Khunte, Gilles Goetz, Chris Limberakis, Amit S. Kalgutkar, Heather Eng, Michael J. Shapiro, Alan M. Mathiowetz, David A. Price, Spiros Liras, Matthew P. Jacobson, and R. Scott Lokey
The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a β-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality.
June 5, 2015
ACS Publications – Organic Letters
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by Andrew T. Bockus, Katrina W. Lexa, Cameron R. Pye, Amit S. Kalgutkar, Jarret W. Gardner, Kathryn C. R. Hund, William M. Hewitt, Joshua A. Schwochert, Emerson Glassey, David A. Price, Alan M. Mathiowetz, Spiros Liras, Matthew P. Jacobson, and R. Scott Lokey
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure–permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.
May 7, 2015
Journal of Medicinal Chemistry
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by Hewitt WM, Leung SS, Pye CR, Ponkey AR, Bednarek M, Jacobson MP, Lokey RS
Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered “undruggable” by typical small molecules. There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side-chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds toward development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.
January 21, 2015
Journal of the American Chemical Society
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by Alan M. Mathiowetz, Siegfried S. F. Leung and Matthew P. Jacobson
Macrocycles have a number of inherent advantages that improve their prospects for achieving oral bioavailability, even when their physical properties lie outside the traditional Rule-of-5 chemistry space. This chapter provides an overview of these advantages, with particular attention given to the potential for macrocycles to adopt three-dimensional conformations that overcome barriers to permeability. An overview of the relationship between physical properties and oral bioavailability is given along with a more detail description of permeability, including recent developments in using fundamental physics to predict passive permeability. A variety of orally bioavailable macrocycles is described, including both natural products and compounds discovered through medicinal chemistry. In addition, some structure property relationships are described, which were identified during the process of optimizing these macrocycles.
October 16, 2014
From the Book: Macrocycles in Drug Discovery
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by Fabrizio Giordanetto and Jan Kihlberg
Macrocycles are ideal in efforts to tackle “difficult” targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 Å2. Moreover, insight from a group of “de novo designed” oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space.
August 28, 2013
Journal of Medicinal Chemistry
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by Bockus AT, McEwen CM, Lokey RS
The structural complexity of many natural products sets them apart from common synthetic drugs, allowing them to access a biological target space that lies beyond the enzyme active sites and receptors targeted by conventional small molecule drugs. Naturally occurring cyclic peptides, in particular, exhibit a wide variety of unusual and potent biological activities. Many of these compounds penetrate cells by passive diffusion and some, like the clinically important drug cyclosporine A, are orally bioavailable. These natural products tend to have molecular weights and polar group counts that put them outside the norm based on classic predictors of “drug-likeness”. Because of their size and complexity, cyclic peptides occupy a chemical “middle space” in drug discovery that may provide useful scaffolds for modulating more challenging biological targets such as protein-protein interactions and allosteric binding sites. However, the relationship between structure and pharmacokinetic (PK) behavior, especially cell permeability and metabolic clearance, in cyclic peptides has not been studied systematically, and the generality of cyclic peptides as orally bioavailable scaffolds remains an open question. This review focuses on cyclic peptide natural products from a “structure-PK” perspective, outlining what we know and don’t know about their properties in the hope of uncovering trends that might be useful in the design of novel “rule-breaking” molecules.
May 21, 2013
Current Topics in Medicinal Chemistry
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Macrocycles and constrained peptides, generally defined as cyclic small molecules or peptides of 500–2,000 Da, have undergone a rebirth over the last five years in drug discovery, due mainly to the introduction of new approaches for their synthesis and screening. This scientific progress has fueled a burst of business activity, with at least 12 biotech companies in the space, of which almost half were founded in the last 5 years.
This special collection from SciBX: Science-Business eXchange provides an overview of the state of the field from both the scientific and the business perspective.
First, in a SciBX Analysis, a roadmap for progress across various platforms is laid out by the participants at a recent SciBX Summit on macrocycles and constrained peptides. The article identifies four areas of science in which work is needed to enable innovation in the field: pharmacokinetics, cell permeability, oral bioavailability and target engagement to develop more drug-like compounds and streamline drug discovery.
This Analysis is complemented by a BioCentury Product Discovery and Development piece that provides a comprehensive overview of the competitive landscape by laying out the players in the field, their partnerships and the status of their most advanced programs.
Next, we provide an introduction to an interactive dashboard produced by Relay Technology Management that allows users to explore trends in grants, publications, company pipelines, transactions and IP relevant to macrocycles and constrained peptides. Relay TM is a strategic partner of Nature Research.
This is followed by a Review by White and Yudin that revisits the latest developments in peptide macrocyclization strategies. The cyclization of macrocycles using traditional chemical synthesis approaches has faced enormous challenges due to steric constraints and the unwieldiness of small and large precursors. But recently, new solutions have emerged, including versatile platforms for macrocycle library generation that open a myriad of new opportunities for generating synthetic macrocycles. A second SciBX Analysis specifically explores the technical and commercial possibilities that may open up based on a new method for creating large libraries of N-methylated peptide macrocycles developed by Suga and collaborators.
Finally, an article by Stewart et al. illustrates the potential of a particular class of constrained peptides called stapled peptides as therapeutic agents. Harnessing the binding precision of stapled peptides, the authors were able to design a highly specific inhibitor of MCL-1, a critical survival factor in a wide range of human cancers.
The Analyses, Reviews and Articles presented here provide a broad overview of the scientific and business status of the field and some examples of specific technological advances that are but a small sample of the possibilities to come.
We acknowledge the support of Aileron Therapeutics Inc., PolyPeptide Group, Polyphor Ltd. and Lanthio Pharma B.V. in producing this collection. Nature Research and BioCentury Publications Inc. have sole responsibility for editorial content
April 2013
Science-Business eXchange
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by Elena Dolghih and Matthew P. Jacobson
In order to reach their pharmacologic targets, successful central nervous system (CNS) drug candidates have to cross a complex protective barrier separating brain from the blood. Being able to predict a priori which molecules can successfully penetrate this barrier could be of significant value in CNS drug discovery. Herein we report a new computational approach that combines two mechanism-based models, for passive permeation and for active efflux by P-glycoprotein, to provide insight into the multiparameter optimization problem of designing small molecules able to access the CNS. Our results indicate that this approach is capable of distinguishing compounds with high/low efflux ratios as well as CNS+/CNS– compounds and provides advantage over estimating P-glycoprotein efflux or passive permeability alone when trying to predict these emergent properties. We also demonstrate that this method could be useful for rank-ordering chemically similar compounds and that it can provide detailed mechanistic insight into the relationship between chemical structure and efflux ratios and/or CNS penetration, offering guidance as to how compounds could be modified to improve their access into the brain.
December 2, 2012
ACS Chemical Neuroscience
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by Rand AC, Leung SS, Eng H, Rotter CJ, Sharma R, Kalgutkar AS, Zhang Y, Varma MV, Farley KA, Khunte B, Limberakis C, Price DA, Liras S, Mathiowetz AM, Jacobson MP, Lokey RS
A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats. In particular, the ionization state of the peptide was examined by the incorporation of naturally occurring amino acid residues that are charged in differing regions of the gut. In addition, data was generated in a variety of in vitro assays and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed.
October 3, 2012
Medicinal Chemical Communications
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