# Cyclic peptide permeability

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $308,000

## Abstract

Cyclic peptides can achieve exquisite biochemical potency and specificity against challenging targets such as
protein-protein interactions (PPIs). Although the size and polarity of most cyclic peptides fail to meet Lipinski's
"Rule of 5" for predicting drug-likeness, a growing number of cyclic peptides have been described that exhibit
the ADME properties of small molecule drugs, including high passive cell permeability and oral bioavailability.
These exceptional cases, which include natural products such as cyclosporine A (CSA) as well as a variety of
model systems developed by our group, have generated enthusiasm for the idea that macrocycles may
provide a “middle way” between small molecules and biologics in the pursuit of challenging intracellular targets.
However, achieving drug-like permeability in cyclic peptides is far from straightforward. Simply removing the C-
and N-termini alone is rarely sufficient for achieving therapeutically relevant cell permeability. Other factors
combine to determine the properties of cyclic peptides, and my group has led the effort to elucidate principles
that govern those properties. This proposal aims to 1) identify novel, lariat and stapled peptides that exhibit
high passive membrane permeability; 2) develop selection strategies for filtering DNA-encoded libraries of
cyclic peptides based on the net polarity of the pendant macrocycles; and 3) use NMR and computational
methods to study the detailed mechanisms of permeability across model lipid bilayers. In Aim 1, we will
synthesize mass-encoded libraries based on lariat and stapled peptide designs, and use methods developed in
my group to evaluate their permeabilities en masse. The results will provide insights into structure-permeability
relationships in this chemical space, as well as providing raw materials for the synthesis of libraries aimed at
biochemical target-based screening. In Aim 2, we will begin by synthesizing a series of DNA-tagged cyclic
peptide test systems in which the permeabilities of the pendant macrocycles, which differ only by
stereochemistry at 2 positions, span nearly two log units. We will test a variety of separation schemes, some of
which are known to separate nucleic acids based on the polarity of covalently attached small molecules. We
will then synthesize a diverse library of ~108 lariat peptides and fractionate the library based on the intrinsic
polarity of the attached peptides. Deep sequencing of the pre- and post-selection libraries will illuminate the
“permeability landscape” in cyclic peptides in the 7-mer to 11-mer size range with unprecedented scope and
breadth. In Aim 3, we will use 1H and 19F 2-D NMR techniques, combined with advanced molecular dynamics
simulations performed by our collaborator, Prof. Sereina Riniker (ETH), to study the detailed mechanisms
underlying passive membrane permeability in cyclic peptides. We will synthesize fluorinated derivatives of CSA
and other model systems and study their transport kine...

## Key facts

- **NIH application ID:** 9840915
- **Project number:** 5R01GM131135-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Robert SCOTT LOKEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840915

## Citation

> US National Institutes of Health, RePORTER application 9840915, Cyclic peptide permeability (5R01GM131135-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840915. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*