Modulation of intracellular protein-protein interactions has been - and remains - a challenging goal for the discovery and development of small-molecule therapeutic agents. The concept of using peptides to modulate intracellular processes has been investigated for decades, as peptides play a central role in every cell in the body. Yet peptides suffer from severe disadvantages. They lack oral bioavailability, their relative inability to cross the cell membrane confines them to extracellular interventions and they are difficult to manufacture. A novel approach to overcome these barriers is to use cystine-knot microprotein (CKM) technology as a vehicle to deliver bioactive peptides. CKMs are endowed with unique and beneficial drug-like properties that could potentially solve critical problems previously plaguing the peptide class of drugs. Due to their small size, CKMs are believed to permeate relatively well through intestinal mucosa. They can be produced via chemical synthesis or recombinant technology relatively inexpensively and in large scale. Some CKMs have demonstrated the ability to enter cells. CKMs are synthetically optimizable and potentially orally bioavailable. Importantly, it is feasible to incorporate pharmacophoric information into the amino acid sequence of a CKM displaying desired features such as high enzymatic stability and good permeation behavior. Therefore, the use of CKMs as pharmacophoric carriers in oral delivery of peptides targeting intracellular protein-protein interactions can become a promising novel approach. We propose studies to assess the suitability of this approach to peptide delivery in well-established model system, using the NBD peptide to selectively target the inflammatory activity of the NF-B signal transduction pathway.

Public Health Relevance

There is a dramatic gap between our understanding of diseases and our ability to treat them because of the limitations inherent in existing drug platforms. Strategies to modulate "undruggable" intracellular processes with bioactive peptides have historically failed because most peptides are inherently unstable and lack membrane permeability. Cystine-knot microproteins (CKMs) are endowed with unique drug-like properties that could potentially solve critical problems previously plaguing the peptide class of drugs. We propose to assess the suitability of the CKM technology as a molecular drug delivery vehicle for oral administration of bioactive peptides targeting intracellular protein-protein interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI098298-01
Application #
8251999
Study Section
Special Emphasis Panel (ZRG1-IMST-M (13))
Program Officer
Prograis, Lawrence J
Project Start
2012-09-07
Project End
2014-02-28
Budget Start
2012-09-07
Budget End
2014-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$229,194
Indirect Cost
Name
Encode Bio, Inc.
Department
Type
DUNS #
623440406
City
Pasadena
State
CA
Country
United States
Zip Code
91103