Project title: Functional characterization of mutations found in genes encoding G-protein-coupled receptors and search for new GPCR ligands
Project No.: lzp-2025/1-0507
Period: 1 January 2026 – 31 December 2028
Project costs: 300 000,00 EUR
Principal Investigator: Dr. biol. Dāvids Fridmanis
Project summary:
GPCRs form one of the largest families of membrane proteins. Their primary function is signal perception and transduction into the cell. GPCRs participate in the regulation of a wide variety of physiological processes. As such, mutations in GPCR-coding genes are linked to numerous hereditary diseases and they are one of the most intensively studied drug targets. Despite their essential role and great interest, many GPCRs still have no known ligand.
Recent advances in high-throughput technologies have significantly changed the overall landscape in research, shifting the focus from functional studies to large-scale data acquisition and analysis. This shift has led to the identification of numerous novel mutations in GPCR genes, but the functional consequences of many remain unclear due to limited experimental validation.
In one of our previous studies, we developed a humanized yeast-based system for peptide ligand screening of GPCRs. Using this platform, we discovered a new allosteric modulator of MC4R as well as performed de-orphanization of the ascidian OXR-like receptor. However, the system’s initial configuration was suitable only for the search of short peptide pharmacophores, but by expanding the randomized peptide space we would significantly enhance its utility.
Therefore, the overall goal of this project is to perform functional characterization of recently discovered GPCR mutations and use the established system to search for orphan human receptor ligands.
Information published 05.01.2026.
Progress of the project:
1 January 2026 – 31 March 2026
According to the plan, the initial stages of the project were devoted to various preparatory work. Thus, within the framework of the second work package, an order was placed for the synthesis of the coding sequences of the selected receptors, the design of oligonucleotides encoding the random peptide library was carried out, and work on the creation of the random peptide library expression plasmid was initiated. Then, within the framework of the third work package, first 14 mutations that were identified during genetic analysis studies were introduced within coding sequence of melanocortin type 4 receptor, these are currently expressed in mammalian cells and their functional characterization has been started. In the subsequent stages of the project implementation, we will start the first ligand selection experiments for the selected orphan receptors, continue our work on the functional characterization of the first 14 receptors, and create the next batch of mutated receptors.
Information published 31.03.2026.