# Using the Ultrastable Cyclotide Scaffold to Modulate Protein-protein Interactions

> **NIH NIH R35** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $412,553

## Abstract

The success of protein-based therapeutics is revolutionizing drug development. Unlike small molecule
drugs, peptide and protein-based therapeutics can target with high selectivity and specificity defective
protein-protein interactions involved in human disease. Despite their success, however, there are still
numerous stability and delivery issues associated with their use as therapeutic agents. For example,
monoclonal antibodies (one the most successful protein-based therapeutics with several blockbuster
drugs on the market and many more in clinical development) can only target extracellular molecular
targets due to their inability to cross biological membranes. They are also extremely expensive to
produce and are not bioavailable due to their susceptibility to proteolytic degradation. These issues
have led to the exploration of alternative protein scaffolds as a source for novel types of protein-based
therapeutics.
 In response to this important challenge, the Camarero lab is using the ultra-stable cyclotide scaffold.
Cyclotides are a new emerging family of large plant-derived backbone-cyclized polypeptides (≈30 amino
acids long) that share a 3 disulfide-stabilized core characterized by an unusual knotted structure. They
have several characteristics that make them ideal drug development tools. The main features of
cyclotides are a remarkable stability due to the cystine knot, a small size making them readily accessible
to chemical synthesis, and excellent tolerance to sequence variations. For example, the first cyclotide to
be discovered, kalataB1, is an orally effective uterotonic, and other cyclotides have been also shown to
be orally bioavailable and capable of crossing cell membranes to efficiently target intracellular
interactions. In addition, cyclotides have been shown to be poorly immunogenic due to their highly
constrained nature. Cyclotides thus appear as highly promising leads or frameworks for peptide drug
design. Within this context, the Camarero lab is also exploring the cell penetrating properties of these
interesting microproteins as well as ways to improve it. Furthermore, his lab is also studying their
pharmacokinetic (PK) and pharmacodynamic (PD) properties and explore different approaches to
improve their PK profiles and oral bioavailability. In addition, we are also exploring the potential of
bioactive cyclotides to be used as selective and specific bioimaging tools for early detection of cancer
tumors.

## Key facts

- **NIH application ID:** 9908124
- **Project number:** 5R35GM132072-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Julio A Camarero
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,553
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908124

## Citation

> US National Institutes of Health, RePORTER application 9908124, Using the Ultrastable Cyclotide Scaffold to Modulate Protein-protein Interactions (5R35GM132072-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9908124. Licensed CC0.

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