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GPCR Ligands
GPCRs are membrane protein receptors that are involved in signal transduction of numerous physiologic processes. GPCRs are by far the largest family of known drug targets. There are approximately 370 GPCRs relevant for drug discovery and development and at least 40% of drugs in the market are thought to act on GPCRs. It is estimated that at least 40 novel endogenous GPCR peptide ligands have yet to be discovered, and there are ample precedents that indicate the high value associated with GPCR peptide ligands. In particular, GPCR peptide ligands have a high probability of being developed into new drugs.
To date, Compugen has identified eight novel peptides that activate G-Protein Coupled Receptors (GPCRs) using a proprietary discovery engine (Shemesh et al., 2008). These GPCR novel peptide ligands were identified by applying a proprietary computational technology to Compugen's proprietary "peptidome". Our peptidome is a collection of thousands of novel human peptide sequences, expected to correspond to natural peptides, and is based on predicting novel cleavage sites in precursor proteins (Kliger et al., 2008).
Applying a machine-learning related technology to our peptidome resulted in a collection of novel peptides likely to activate GPCRs. Thirty three peptides, all novel, were synthesized and screened in a functional assay against a panel of 152 GPCRs. Eight peptides were shown to activate six different GPCRs in a concentration-dependent manner, including some for which there are no known endogenous ligands. The receptors for which novel ligands have been discovered include the MAS1 and MAS-related GPCRs, MRGX1 and MRGX2, as well as FPRL1 (Hecht et al., 2008) and two of the Relaxin family receptors, RXFP1 and RXFP2.
We intend to utilize the platform on a larger scale, synthesizing and validating more peptides, in order to discover additional novel ligands. We seek to do this in collaboration with a pharma or biotech partner. We will also seek joint development and licensing opportunities around current and future novel ligands we have discovered. Compugen has an agreement with Merck based on the GPCR platform. |
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