This project frames into the quest for antibiotics with novel scaffolds and mechanism of action, and for novel compounds with anti-inflammatory and anti-oxidative activity. We will evaluate the biological properties of compounds that include analogues/derivatives of L-glutamate, L-cysteine and L-homocysteine (HCys).
The mechanism through which compounds containing C-P-H bonds (phosphinic), patented as antibiotics, exert their activity still needs to be elucidated. The approach will be mostly metabolomic and proteomic.
The C-S containing compounds will be tested for anti-inflammatory, anti-oxidative and antiangiogenic activities. Some of these compounds include the oxidized forms of HCys and their derivatives that accumulate in patients when the methionine recycling pathway becomes impaired, as in cardiovascular diseases, neurological/psychiatric disorders and cancer. We synthesized chemically homocysteinsulfinic acid and established that it can be converted to homohypotaurine (HHT), a compound commercially not available, via an enzymatic, bio-based route. The best conditions for the bio-based synthesis and purification of HHT will be established and the compound tested on cardiomyocytes, HUVEC cells and neutrophils.
Furthermore, we will investigate the metabolic role of C-S-containing biomolecules related to taurine. Particular emphasis will be on thiotaurine, a biomolecule releasing hydrogen sulfide (H2S), and on the role of these molecules in controlling inflammation. The specific signaling pathways involved will be dissected and the enzymatic route to its synthesis will be investigated. We aim to identify the proteins that change their expression level or undergo post-translational modifications, including nitrosylation/nitration, persulfidation. Finally, the effect of H2S will be assessed in pathologies characterized by an increase of oxidative stress, as it occurs in some respiratory diseases such as Chronic Obstructive Pulmonary Disease.
