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New Strategy Rapidly Identifies Two Prototype Drugs

A new and comprehensive drug development strategy that starts with extensive screening of potential targeting peptides to rapidly identify prototype small-molecule drugs has produced two that target the EGFR and VEGFR pathways in novel ways, according to a research team led by scientists at The University of Texas M.D. Anderson Cancer Center "The conceptual advance here is to demonstrate how to go rapidly from screening to structural-functional analysis to drug prototype in a few years," said co-senior author Dr. Wadih Arap, of the David H. Koch Center at M.D. Anderson. "The practical outcome is a pair of new drug candidates, one that acts as a decoy to inhibit a cancer-promoting pathway and another that blocks angiogenesis (the development of new blood vessels), which has the potential to treat both cancer and retinopathies that cause blindness," said co-senior author Dr. Renata Pasqualini, also of the David H. Koch Center. The group's approach begins by screening the target receptors with a phage display library used by Drs. Arap and Pasqualini. This method screens billions of viral particles that each display a different peptide on its outer coat to find those that fit into the receptor as a key goes into a lock. Candidate peptides are next winnowed by using structural and functional analysis. Once a peptide is identified and tested, the researchers take an additional step to synthesize a new version of the peptide more suited for use as a drug.

L-amino acids and proteins are the building blocks of life, but are easily degraded by cellular protein recycling machinery, making peptide-based drugs more vulnerable to destruction. Through a process called retro-inversion, the group chemically synthesizes a mirror image peptidomimetic using D-amino acids along with a reversed peptide sequence. The resulting products are more durable, but still target the receptor.

For example the peptide that targets VEGFR is called RPL, letters that represent three natural amino acids that make up the peptide. The retro-inverted D-peptidomimetic is D(LPR). For the EGFR decoy, the natural peptide CVRAC becomes the D-peptidomimetic D(CARVC).

The two prototype drugs will need to be further refined in preclinical models and later tested in clinical trials before they can become available for general use.

These results are described in back-to-back papers published online in PNAS. [Press release]