Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets

2017-10-18T18:12:11+00:00 October 18th, 2017|by our Team Members, Publications|

by Matthew R. Naylor, Andrew T. Backus, Maria-Jesus Blanco, Scott Lokey Highlights

  • The pursuit of ‘undruggable’ therapeutic targets has reinvigorated interest in natural products.
  • Peptides have been traditionally considered poor pharmaceutical candidates.
  • Some large cyclic peptide natural products have proven bioactivity and oral bioavailability.
  • Cyclic peptides have been synthesized to explore ADME optimization.
  • […]

Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators.

2017-10-18T17:35:18+00:00 October 18th, 2017|by our Team Members, Publications|

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 ABSTRACT: The chemokin […]

Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules

2017-09-25T14:46:59+00:00 January 6th, 2017|by our Team Members, Publications|

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. Usi […]

Passive Membrane Permeability in Cyclic Peptomer Scaffolds Is Robust to Extensive Variation in Side Chain Functionality and Backbone Geometry

2017-09-19T11:47:52+00:00 October 3rd, 2016|by our Team Members, Publications|

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 librar […]

Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides

2017-09-19T11:49:36+00:00 June 6th, 2016|by our Team Members, Publications|

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 permeabil […]

Simple Predictive Models of Passive Membrane Permeability Incorporating Size-Dependent Membrane-Water Partition

2017-09-26T11:28:09+00:00 May 23rd, 2016|by our Team Members, Publications|

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 regress […]

Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues

2017-09-19T11:41:12+00:00 August 26th, 2015|by our Team Members, Publications|

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 gr […]

Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products

2017-09-19T11:58:18+00:00 June 12th, 2015|by our Team Members, Publications|

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 […]

Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides

2017-09-19T11:32:50+00:00 June 5th, 2015|by our Team Members, Publications|

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 mai […]