Design, Synthesis and Biological Evaluation of New Transglutaminase 2 Inhibitors and ZetaCOP1 - gammaCOP1 Interaction Disrupters

Section I: A newly established strategy of drug discovery, termed “multitarget ligands” drug design, resulted as an alternative concept to the classic “one disease-one target” method and a more suitable approach for multifactorial diseases’ treatment. This section considers diverse potential targets/events involved in Alzheimer’s disease, including Transglumitase 2 (TG2), Histone Deacetylases (HDACs), oxidative stress, GSK3β and amyloid aggregation, and illustrates the design and development of multitarget ligands targeting simultaneously towards two targets/events: the first series of compounds, consisting of a TG2 inhibitor core structure coupled to hydroxamic acid moiety, were potential TG2-HDAC dual inhibitors and showed interesting profile in preliminary studies, with compound 3 being a low micromolar inhibitor of TG2 and good inhibitor for HDACs; the second series of compounds derived by merging the same core structure with a polyphenol moiety to give potential TG2 inhibitors/antioxidants. Within this series, compound 22 was the most promising derivative with good antioxidant activity and a balanced inhibition profile on GSK3β and Aβ self-aggregation. Section II: Coat protein I (COPI) is a coatomer protein complex and represents the major component of vesicles that mediate the intracellular retrograde transport. A subunit of this protein complex, known as ζCOP1, was identified as a promising cancer target: its knockdown by siRNA causes tumor-specific growth inhibition without affecting the viability of normal cells. Therefore, a correct function of ζCOP1 is crucial for the survival of tumor cells and compounds capable of interfering with the biological function of ζCOP1 could exert selective antitumor activity. Since the main function of ζCOP1 is to form a dimer with γCOP1 within the coatomer complex, disrupters of this ζCOP1/γCOP1 protein-protein interaction (PPI) could impair the correct function of ζCOP1, thus, being potential anticancer drugs. This section focuses on the design and development of cyclic peptide-based compounds as potential disrupters of ζCOP1/γCOP1 PPI.