In 2005, two chemists decided to work together to develop libraries of cyclic peptides—strings of amino acids formed in the shape of a circle—that could be used to treat a range of infectious diseases, autoimmunity and cancer. Thanks to their flexibility, these cyclic peptides can access different parts of a protein target and so bind to …
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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
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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
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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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Read online article by Ron Leuty, Reporter at San Francisco Business Times
Startup Circle Pharma Inc., a UCSF and UC Santa Cruz spinout devising ways to disrupt a wide variety of diseases from inside cells, will work with Pfizer Inc. on two drug programs.
The financial value of the collaboration, as well as the amount of seed funding Circle received this summer from Pfizer and Mission Bay Capital LLC, wasn’t disclosed.
The companies also didn’t specify the two targets that are central to the collaboration.
Still, the deals are huge for Circle — after all, it’s not every day that the world’s largest drug company opts to collaborate with and fund a startup. What’s more, the deal validates the San Francisco company’s coupling of synthetic chemistry with computational design algorithms to select drugs that can slip through cell membranes to attack diseases.
But the deals also are big wins for QB3, also known as the California Institute for Quantitative Biosciences, which aims to commercialize academic work out of the University of California, Berkeley, UCSF and UC Santa Cruz.
Circle’s founders — UCSF School of Pharmacy professor Matt Jacobson and Scott Lokey, a professor of chemistry and biochemistry at UC Santa Cruz — linked up with Pfizer a few years ago through one QB3 program. The company formed with the help of another QB3 program, and it assembled its business plan through yet another QB3-related endeavor.
Even Mission Bay Capital is connected to QB3, managed by QB3 director Regis Kelly and associated director Douglas Crawford, to invest in UC life sciences startups.
“This is an ideal (outcome) — from sponsored research to startup. It’s a cool model,” said Neena Kadaba, director of industry alliances with QB3. “The idea is to pull in startups that are invisible to pharma partners.”
Circle’s work centers on macrocyclic peptides, or strings of amino acids formed into circles. Those molecules potentially could address many diseases that can’t be hit today with conventional small-molecule drugs or large-molecule biologics.
Most therapies require a place on the surface of a cell where a drug can land and attach — a so-called binding site — but macrocyclic peptides can bypass binding sites by wiggling directly into cells. That permeability makes macrocycles attractive for attacking “undruggable” diseases, said Circle Pharma President and CEO David Earp, as well as cancers, fibrosis, inflammation and infection.
The challenge for several companies that have jumped into the field over the last half-dozen years is that they find a macrocycle that works against the disease in theory but ultimately can’t get the macrocycle into the cell.
Circle Pharma, Earp said, understands the physics of the molecules, how they adapt within and outside of the cell and how they interact with proteins. While macrocycles could help carry existing drugs into cells and be more effective once inside, Circle is focusing on developing new drugs — initially for Pfizer, but eventually for other partners and itself — rather than reshaping old ones.
Pfizer (NYSE: PFE) understood Jacobson and Lokey’s computational approach to macrocycles right away, Earp said. It funded the duo’s research through a QB3-Pfizer program that links drug makers and academics.
QB3 also worked with Jacobson and Lokey through another program, called Startup in a Box, to get Circle Pharma incorporated and ready to go. It also helped Jacobson and Lokey, who are QB3 faculty, apply for federal Small Business Innovation Research awards that became manna for biotech startups deserted by venture capital funders during the biotech industry’s roughly five-year financial drought that started in 2007.
Around that time, QB3’s Crawford called Earp, who left Geron Corp. (NASDAQ: GERN) after 13 years as chief legal officer, senior vice president of business development and other positions. Crawford asked if Earp would be interested in advising academics through the complexities of setting up new companies.
One of those companies would be Circle.
“The power of the technology was apparent in theory,” Earp said, “but it’s something different to take an academic project into a company environment with timetables and limited resources — sometimes more limited than the academic environment.”
Yet Circle has met those challenges and now is what Earp calls a “rational drug development company.”
Kadaba of QB3 calls Circle validation of the institute’s work to move potential therapies from lab bench to bedside. But, she added, it also shows that companies need more than an encouraging word and a pat on the head from Big Pharma.
“Startups need more than just, ‘Here’s the target and we’ll come back and be interested in two years,’” she said. “They need, ‘Here’s the data you need to generate and here’s $300,000 to go do it.’ They need pharma partners that are engaged.”
Circle Pharma, Inc., a newly created, early-stage biotechnology company, today announced that it has received seed funding from Pfizer Inc. and QB3’s seed-stage venture fund, Mission Bay Capital, LLC, and has initiated two collaborations with Pfizer to develop cell permeable macrocyclic peptide therapeutics.
“We are very pleased to have launched Circle with the backing of Pfizer and Mission Bay Capital, and to have initiated two exciting collaborative projects with Pfizer,” said David J. Earp, J.D., Ph.D., Circle’s President and CEO. “In addition to these collaborations, Circle will be undertaking development work against our own therapeutic targets. We are open to additional collaborations with partners who share our excitement in the potential of permeable macrocyclic peptides, which, we believe, could be applicable to a large number of important therapeutic targets.”
Circle’s technology is based in part on research sponsored by Pfizer through an agreement with QB3.
About Macrocyclic Peptides
Macrocyclic peptides have the potential to provide access to therapeutic targets that are considered undruggable with conventional small molecule or biologic modalities. In particular, there is great interest in developing macrocycles to modulate protein-protein interactions, which play a role in almost all disease conditions, including cancer, fibrosis, inflammation and infection. However, the development of macrocyclic therapeutics has been limited to this point by the need for a greater understanding of how to design macrocycles with appropriate pharmacokinetics, cell permeability and oral bioavailability. Indeed, today, most clinical programs testing macrocyclic peptides are aimed at extracellular protein targets because of the challenge of identifying cell permeable macrocycles. The ability to design potent macrocycles with inherent permeability is expected to give access to a large number of important therapeutic targets that have been out of reach to this point.
About Circle
Circle Pharma is an early stage biotechnology company applying proprietary computational design algorithms and innovative chemistry to develop cell permeable macrocycle peptide therapeutics against important clinical targets. It does this through an iterative, rational design process that deploys large virtual libraries of conformationally diverse macrocycle scaffolds selected for inherent permeability. The company was founded by Prof. Matt Jacobson, Ph.D. (U.C. San Francisco) and Prof. Scott Lokey, Ph.D. (U.C. Santa Cruz) and is headed by David J. Earp, J.D., Ph.D.
September 22, 2014, San Francisco
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