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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
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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
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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
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Circle Pharma, Inc. today announced that it has completed an expansion of its Series A financing, with new investors W.I. Harper Group, Elements Partners, LLC, Whitesun Healthcare Ventures Limited and LifeForce Capital joining the round. Mission Bay Capital led Circle’s Series A, with Pfizer Inc. (NYSE:PFE), ShangPharma Investment Group, Ltd. and a syndicated group of individual investors subscribing at the initial close. With this subsequent closing, a total of approximately $6.5M of shares of Circle’s Series A Preferred Stock has been issued in the Series A financing.
“We are gratified to have this new group of high-caliber investors joining our first equity financing,” said David J. Earp, J.D., Ph.D., Circle’s president and CEO. “The funds will support Circle’s platform development and our therapeutic pipeline, which is focused on intracellular protein-protein interactions that are key drivers in oncogenic pathways. This is an exciting time for Circle. We are adding new targets to our pipeline, including MCL1 and the substrate binding site of cyclinA / cdk2, both of which are important oncology targets that have proven challenging for small molecule drug development. Our chemistry process development work has recently successfully achieved key steps required for a more highly automated synthesis platform. Finally, with support from Pfizer, we are building a physical library of macrocycles which are predicted to have optimized permeability. This library will complement our rational design/virtual library screening approach. We will begin synthesis of the physical library shortly, enabling us to deliver it to Pfizer, and potentially other collaborators, for screening use later this year. We are especially delighted to welcome James Lu to our board in connection with this expanded Series A investment. He brings deep experience building high-growth, global companies both as an investor and in management roles.”
Mr. Lu is a Managing Director of WI Harper, a cross border venture capital firm investing in leading healthcare and technology startups in the U.S. and China. Previously, Mr. Lu co-founded and was a General Partner of iD Ventures America (formerly Acer Technology Ventures), which managed several funds that were early investors in companies such as iRobot (NASDAQ:IRBT); Harmonix Music (acquired by MTV/Viacom (NYSE:VIA)); and Monolithic Power Systems (NASDAQ:MPWR). In prior roles, Mr. Lu was General Counsel of the Acer Group and earlier was a corporate and commercial attorney with the McCutchen law firm in San Francisco and a banker at JP Morgan in New York. Mr. Lu graduated with a BA from Yale College, an MBA from Harvard Business School and a JD from UC Berkeley School of Law.
Peter Liu, Founder and Chairman of WI Harper Group commented “we are seeing excellent opportunities for investing in ground-breaking life science companies that are advancing new technologies and addressing unsolved problems. Circle Pharma is one such company; we are pleased to participate in their Series A financing and look forward to building a strong relationship with the management team and the other investors.”
“Completion of Circle’s Series A financing strengthens Circle’s investor base and brings additional depth on the technical side, relations with strategic partners and, with WI Harper and Elements, connections to activities and initiatives outside of the U.S., and especially in key Asia markets,” said Douglas Crawford, Ph.D., managing director of Mission Bay Capital.
About Macrocyclic Peptides
Macrocyclic peptides have the potential to allow drug developers to address the large proportion of known therapeutic targets (estimated at up to 80%) 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 by the need for a greater understanding of how to develop macrocycles with appropriate pharmacokinetics, cell permeability and oral bioavailability. Circle is applying its ability to design potent macrocycles with intrinsic cell permeability and drug-like characteristics to unlock access to challenging, high value therapeutic targets that have been out of reach to other approaches.
About Circle Pharma, Inc.
Circle is developing a new paradigm for macrocycle drug discovery based on rational design and synthetic chemistry. Circle’s technology facilitates the design and synthesis of intrinsically cell- permeable macrocycles that can address both intra- and extra-cellular therapeutic targets, and can be delivered by oral administration. Circle’s macrocycle development platform is applicable across a wide range of serious diseases; the company is initially focusing its internal development efforts on intracellular protein-protein interactions that are key drivers in cancer. Circle’s founders are Prof. Matthew P. Jacobson (Chair of the Dept. of Pharmaceutical Chemistry at UC San Francisco and co- founder of Global Blood Therapeutics (NASDAQ: GBT) and Relay Therapeutics) and Prof. R. Scott Lokey (Dept. of Chemistry and Biochemistry, UC Santa Cruz and director of the UCSC Chemical Screening Center).
South San Francisco, CA, April 25, 2017
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
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Circle Pharma, Inc. today announced a Series A financing round in which it has issued over $4.5M of shares of Series A Preferred Stock. The financing was led by Mission Bay Capital, with Pfizer Inc. (NYSE:PFE), ShangPharma Investment Group, Ltd. and a syndicated group of individual investors joining the round. In connection with the financing, Walter H. Moos, Ph.D., representing ShangPharma, has joined the Circle Board of Directors.
“We are delighted with the participation of such high caliber investors in our first equity round,” said David J. Earp, J.D., Ph.D., Circle’s president and CEO. “With our seed funding, we established Circle’s computational design platform, advanced our synthetic chemistry capabilities in collaboration with ChemPartner, and engaged in a target-based collaboration with Pfizer. The Series A funds will be used to support Circle’s therapeutic pipeline, which is focused on intracellular protein-protein interactions that are key drivers in oncogenic pathways. We are also now building a physical library of cell- permeable macrocycles to augment our computational design tools, and this library will later be available to our collaboration partners. We are particularly excited to welcome Walter Moos to our Board of Directors. Dr. Moos brings a wealth of life sciences R&D experience, having served most recently as the president of SRI Biosciences and previously in senior executive roles at MitoKor, Chiron and Warner-Lambert/Parke-Davis. His teams have advanced numerous pharmaceutical products from discovery to commercialization, and we are fortunate to have him join Circle.”
“I am very much looking forward to taking an active role on Circle’s board,” said Walter Moos. “The combination of innovative technology and the great team at Circle could help unlock high value targets that have long been considered out of reach of drug developers.”
Dr. Moos has served on about 20 business and scientific boards, including Amunix, Oncologic (Aduro), Onyx (Amgen), Rigel and the Biotechnology Industry Organization (BIO).
About Macrocyclic Peptides
Macrocyclic peptides have the potential to allow drug developers to address the large proportion of known therapeutic targets (estimated at up to 80%) 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 by the need for a greater understanding of how to develop macrocycles with appropriate pharmacokinetics, cell permeability and oral bioavailability. Circle’s ability to design potent macrocycles with intrinsic cell permeability could unlock access to challenging, high value therapeutic targets that have been out of reach to other approaches.
About Circle Pharma, Inc.
Circle is developing a new paradigm for macrocycle drug discovery based on rational design and synthetic chemistry. Circle’s technology facilitates the design and synthesis of intrinsically cell- permeable macrocycles that can address both intra- and extra-cellular therapeutic targets, and can be delivered by oral administration. Circle’s macrocycle development platform is applicable across a wide range of serious diseases; the company is initially focusing its internal development efforts on intracellular protein-protein interactions that are key drivers in cancer. Circle’s founders are Prof. Matthew P. Jacobson (Chair of the Dept. of Pharmaceutical Chemistry at UC San Francisco and co- founder of Global Blood Therapeutics (NASDAQ: GBT) and Relay Therapeutics) and Prof. R. Scott Lokey (Dept. of Chemistry and Biochemistry, UC Santa Cruz and director of the UCSC Chemical Screening Center).
December 21, 2016, South San Francisco
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
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CirclePharma, Inc., today announced that it will apply its computational design and synthetic chemistry platform to design and create a physical screening library of novel macrocyclicpeptides. Once completed, the library is initially expected to comprise several hundred macrocycles that will be designed to potentially disrupt bioactive conformations commonly found in protein-protein interactions known to drive disease processes, and will deploy backbone scaffolds screened in silica for intrinsic cell permeability characteristics. In addition, the design of the library will permit the simple creation of derivative libraries tailored to specific features of a therapeutic target class.
PfizerInc.(NYSE:PFE) has entered into an agreement with Circle under which Pfizer will provide support for the library build, and Circle has granted Pfizer non-exclusive rights to screen the library against certaintargets. The rights granted to Pfizer exclude specified targets for which Circle has reserved exclusive rights to screen the library.
“This physical library will complement Circle’s target-specific computational design toolkit,” said David J. Earp, J.D., Ph.D., Circle’s President and CEO. “We expect to use the library for our internal pipeline discovery work, and we will make it available to all of our collaboration partners in drug discovery.”
About Macrocyclic Peptides
Macrocyclic peptides have the potential to provide access to the large proportion of therapeutic targets (estimated at up to 80%) that are considered undruggable with conventional small molecule or biologic modalities. Inparticular, 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 pharm acokinetics, cell permeability and oral bioavailability. As a result, most clinical-stage macro cyclic peptide drugs address extracellular protein targets because of the challenge of identifying cell permeable macrocycles. The ability to design potent macrocycles with intrinsic 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 Pharma
Founded by computational chemist Prof. Matthew Jacobson (UC San Francisco) and peptide chemist Prof. Scott Lokey (UC Santa Cruz), Circle Pharma is developing a new paradigm for macrocycle drug discovery. Circle’s technology facilitates the design and synthesis of intrinsically cell-permeable macrocycles that can address both intra- and extra-cellular therapeutic targets, and can be delivered by oral administration. Circle’s macrocycle development platform is applicable across a wide range of serious diseases; the company is initially focusing its internal development efforts on intracellular protein-protein interactions that are key drivers in cancer.
September 12, 2016, South San Francisco, CA
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
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