Designing new drugs is a laborious and painstaking process. That’s partly because scientists must first thoroughly understand the chemical structure of a drug’s intended target – frequently a complex protein – and figure out the most effective way to modify it.
Researchers design small-molecule drugs so they’ll fit tightly with part of a targeted protein – sometimes a geometrically flat surface, other times a “pocket” or other structural feature that the drug can attach to and effectively stop at least one of the protein’s functions.
In many diseases, particular genes are overexpressed, and a proliferation of their protein products leads to tissue damage. That’s the case with a protein called Siah, which regulates important functions inside the cell but also plays a role in the development and progression of cancer. Selectively inhibiting the Siah protein where it’s malfunctioning may provide another weapon in our arsenal to fight cancer.
In a new study, researchers at Sanford-Burnham led by Maurizio Pellecchia, Ph.D., professor in our Infectious and Inflammatory Disease Center, have developed a new peptide – a small chain molecule – especially designed to inhibit Siah by “docking” at a particular site on the protein’s surface.
“Obtaining inhibitors that are potent, selective, and that have a clear mechanism of binding and action is not a trivial accomplishment,” Pellecchia said. “Our study represents a first, yet pivotal stepping stone toward further validating Siah as a target for novel anticancer therapies.”
The peptide alters how Siah regulates two signaling pathways, called Erk and Hif, which promote the development of cancer when they malfunction. Inhibiting Siah also may have other benefits – the protein appears to play a role in Parkinson’s disease.
In their study, Pellecchia and his colleagues screened 16,900 compounds from an in-house collection and also mined two separate libraries of peptides from the Torrey Pines Institute for Molecular Studies. Moreover, a parallel effort from our Conrad Prebys Center for Chemical Genomics tested over 300,000 compounds from the National Institutes of Health library in an HTS campaign. None worked.
The team then tested a carefully engineered peptide that would form a stable chemical bond with an amino acid called cysteine in one of the pockets of the Siah protein. After showing as a “proof of principle” that the bond worked with a chemically modified Siah protein, the team found a similar binding site on the naturally occurring “wild type” Siah protein. They further modified the peptide to bond effectively to the newly found site.
This peptide can now be used as a chemical probe to further explore the role of Siah in the formation of cancer tumors, and also to validate Siah as a target for anticancer therapies, the authors wrote. “In collaboration with Dr. Ze’ev Ronai, we have preliminary shown that the peptide is able to reduce tumor growth in a mouse model of melanoma,” Pellecchia added. “We are currently developing further improved Siah inhibitors that ensure that these agents can more efficiently enter cells hence enabling further in vivo efficacy experiments”. The particular design they developed may represent a novel route for the optimization of these molecules into more effective peptide-based therapeutics.
John L. Stebbins, Eugenio Santelli, Yongmei Feng, Surya K. De, Angela Purves, Khatereh Motamedchaboki, Bainan Wu, Ze’ev A. Ronai, Robert C. Liddington, & Maurizio Pellecchia (2013). Structure-Based Design of Covalent Siah Inhibitors Chemistry & Biology DOI: 10.1016/j.chembiol.2013.06.008