Protein disulfide isomerases (PDIs) are redox chaperone proteins that belong to the thioredoxin oxidoreductase superfamily and are able to catalyze dithiol-disulphide exchange reactions.1 In the last years, the scientific community paid much attention to PDIA3 isoform, because altered expression and activity of this protein has been associated with several human diseases, such as cancer, neurodegenerative diseases, and also viral infection.2 Indeed, the presence of PDIA3 on the cell surface has been related with the entry of different viruses in human cells. During influenza A virus (IAV) infection, PDIA3 is involved in the hemagglutinin protein maturation and IAV replication, suggesting a potential role as target to counteract IAV infection. Moreover, in human coronaviruses (HCoVs), PDIA3 is associated with the effective oxidative folding and trimerization of HCoV Spike (S) protein by catalyzing the formation of disulphide bonds that could mediate the interaction between the envelope and S protein. Therefore, PDIA3 may be viewed as an interesting pharmacological target with a huge potential for the development of innovative antiviral agents. Also considering its presence in human cells and not in the viruses, PDIA3 offers the opportunity to discovery new drugs as putative broad- spectrum antiviral agents, overcoming problems such as drug resistance. In previous studies, 16F16 was reported as a covalent inhibitor of PDIA1 and PDIA3 proteins due to the presence of a chloroacetyl group that irreversibly binds to free cysteine thiols.3 Starting from the chemical structure of 16F16, we designed and synthesized a small set of structural analogues, characterized by a tetrahydro-β-carbolines core endowed with a chloroacetyl group in 2-position as PDIA3 inhibitors, to further explore the structure activity relationship. The data coming from the biochemical assays will be shown and discussed.
Identification of new heterocyclic compounds as protein disulfide isomerase A inhibitors / Ialongo, D.; Messore, A.; Madia, V. N.; Patacchini, E.; Ruggieri, G.; Albano, A.; Arpacioglu, M.; Scipione, L.; Altieri, F.; Paglia, G.; Meschiari, G.; Di Santo, R.; Costi, R.. - (2024). (Intervento presentato al convegno SCI 2024 Chemistry ELEMENTS OF FUTURE - XXVIII Congresso Nazionale della Società Chimica Italiana tenutosi a Milan, Italy).
Identification of new heterocyclic compounds as protein disulfide isomerase A inhibitors.
Ialongo, D.;Messore, A.;Madia, V. N.;Patacchini, E.;Albano, A.;Arpacioglu, M.;Scipione, L.;Altieri, F.;Paglia, G.;Meschiari, G.;Di Santo, R.;Costi, R.
2024
Abstract
Protein disulfide isomerases (PDIs) are redox chaperone proteins that belong to the thioredoxin oxidoreductase superfamily and are able to catalyze dithiol-disulphide exchange reactions.1 In the last years, the scientific community paid much attention to PDIA3 isoform, because altered expression and activity of this protein has been associated with several human diseases, such as cancer, neurodegenerative diseases, and also viral infection.2 Indeed, the presence of PDIA3 on the cell surface has been related with the entry of different viruses in human cells. During influenza A virus (IAV) infection, PDIA3 is involved in the hemagglutinin protein maturation and IAV replication, suggesting a potential role as target to counteract IAV infection. Moreover, in human coronaviruses (HCoVs), PDIA3 is associated with the effective oxidative folding and trimerization of HCoV Spike (S) protein by catalyzing the formation of disulphide bonds that could mediate the interaction between the envelope and S protein. Therefore, PDIA3 may be viewed as an interesting pharmacological target with a huge potential for the development of innovative antiviral agents. Also considering its presence in human cells and not in the viruses, PDIA3 offers the opportunity to discovery new drugs as putative broad- spectrum antiviral agents, overcoming problems such as drug resistance. In previous studies, 16F16 was reported as a covalent inhibitor of PDIA1 and PDIA3 proteins due to the presence of a chloroacetyl group that irreversibly binds to free cysteine thiols.3 Starting from the chemical structure of 16F16, we designed and synthesized a small set of structural analogues, characterized by a tetrahydro-β-carbolines core endowed with a chloroacetyl group in 2-position as PDIA3 inhibitors, to further explore the structure activity relationship. The data coming from the biochemical assays will be shown and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
