Investigating Small Molecule Modulators of PKM2 Tetramerization

Psoriasis is distinguished by persistent cutaneous inflammation and has discernible clinical signs as an autoimmune disease. In comparison to those residing from other global areas, whose susceptibility stands at a mere 2%, individuals of Northern European and Caucasian descent have a much higher vulnerability rate of 11%. The psoriasis imiquimod-induced model may be reversed in mice that lack the glycolytic protein pyruvate kinase isoform II (hPKM2), particularly in keratinocytes, or when this enzyme is regulated by pharmaceutical treatments. The dimeric form of hPKM2 is responsible for the execution of non-canonical processes, namely the upregulation of pro-inflammatory cytokines. The dissociation of PKM2 into lower oligomeric forms has been shown to activate the IL-17 pathway, which plays a crucial role in the development of psoriasis and may be regulated by allosteric effectors. The identification of compounds that inhibit the disassembly of the hPKM2 tetrameric oligomer into dimers/monomers is of crucial significance in hindering the advancement of the illness. The objective in this context is to identify and develop novel therapeutic agents for the treatment of psoriasis. Differential scanning fluorimetry (DSF) is a method used to assess the thermal response of proteins. It enables the detection of changes in protein conformation and stability in the face of changes in temperature. Consequently, the enhanced thermal stability seen in the presence of ligands (specifically tetramer) may be attributed to the formation of higher oligomeric states of hPKM2. This work presents the outcomes of an extensive investigation on tetramerization modulators. The research included the screening of a total of 8000 compounds using hPKM2 thermal stability as the primary criterion. From this screening, a subset of 127 compounds displaying attractive results were selected for further analysis. A multitude of biochemical and biophysical studies have been conducted to ascertain the manner in which the wild-type protein reacts to the presence of these ligands. At now, the evaluation of tetramerization and cellular activity is being conducted for the top 26 candidates that have the highest potential. Moreover, the technique of x-ray crystallography has been used to investigate the process by which the ligand binds. The evaluation of the best cellular therapies for psoriasis will be conducted in animal models produced with imiquimod, in accordance with appropriate study protocols.