Protein disulfide isomerases (PDIs) are multifunctional redox chaperone that belong to the thioredoxin oxidoreductase superfamily and catalyze dithiol-disulphide exchange reactions. In humans, the PDI family is composed of 21 members classified by sequence and structural homology.1 The most famous member of thiol isomerase family is PDIA1, and it is structurally characterized by two thioredoxin-like active domains (a, a′), two substrate-binding domains (b, b′) with a hydrophobic pocket in the b′ domain, a linker sequence between the b′ and the a′ domains, and a C-terminal extended domain.2 PDIA3, also known as ERp57 or glucose regulated protein, shows a high similarity in the catalytic domain a and a’ with PDIA1. However, notable differences concerning their different cellular biochemical roles in cellular homeostasis exist. ERp57/PDIA3 is involved, as the other PDIs, in the proper folding and in the formation and reshuffling of the disulfide bridges of the proteins synthesized in the rough ER. Several studies have shown that altered expression and activity of PDIA3 is associated with several human diseases, such as cancer, neurodegenerative diseases, hepatitis, metabolic diseases, musculoskeletal system conditions, viral infection, and PDIA3 expression level has been evaluated as a useful biomarker for diagnosis and/or prognosis in several conditions. Indeed, the presence of PDIA3 on the cell surface has been related with the entry of different viruses. In human coronaviruses (HCoVs), PDIA3 is known to be involved in 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. Moreover, 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. Therefore, PDIA3 may be an interesting pharmacological target with a huge potential for the development of antiviral agents. In previous studies, 16F16 was reported as an irreversible inhibitor of PDIA1 and PDIA3 proteins due to the presence of a chloroacetyl group that covalently modifies 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.
Targeting protein disulfide isomerase A with newly designed and synthesized aryl derivatives / Albano, A.; Madia, V. N.; Ruggieri, G.; Ialongo, D.; Patacchini, E.; Arpacioglu, M.; Messore, A.; Scipione, L.; Altieri, F.; Paglia, G.; Meschiari, G.; Di Santo, R.; Costi, R.. - (2024). (Intervento presentato al convegno EFMC-YMCS 2024 11th EFMC Young Medicinal Chemists' Symposium tenutosi a Rome).
Targeting protein disulfide isomerase A with newly designed and synthesized aryl derivatives
Albano, A.
;Madia, V. N.;Ialongo, D.;Patacchini, E.;Arpacioglu, M.;Messore, A.;Scipione, L.;Altieri, F.;Paglia, G.;Meschiari, G.;Di Santo, R.;Costi, R.
2024
Abstract
Protein disulfide isomerases (PDIs) are multifunctional redox chaperone that belong to the thioredoxin oxidoreductase superfamily and catalyze dithiol-disulphide exchange reactions. In humans, the PDI family is composed of 21 members classified by sequence and structural homology.1 The most famous member of thiol isomerase family is PDIA1, and it is structurally characterized by two thioredoxin-like active domains (a, a′), two substrate-binding domains (b, b′) with a hydrophobic pocket in the b′ domain, a linker sequence between the b′ and the a′ domains, and a C-terminal extended domain.2 PDIA3, also known as ERp57 or glucose regulated protein, shows a high similarity in the catalytic domain a and a’ with PDIA1. However, notable differences concerning their different cellular biochemical roles in cellular homeostasis exist. ERp57/PDIA3 is involved, as the other PDIs, in the proper folding and in the formation and reshuffling of the disulfide bridges of the proteins synthesized in the rough ER. Several studies have shown that altered expression and activity of PDIA3 is associated with several human diseases, such as cancer, neurodegenerative diseases, hepatitis, metabolic diseases, musculoskeletal system conditions, viral infection, and PDIA3 expression level has been evaluated as a useful biomarker for diagnosis and/or prognosis in several conditions. Indeed, the presence of PDIA3 on the cell surface has been related with the entry of different viruses. In human coronaviruses (HCoVs), PDIA3 is known to be involved in 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. Moreover, 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. Therefore, PDIA3 may be an interesting pharmacological target with a huge potential for the development of antiviral agents. In previous studies, 16F16 was reported as an irreversible inhibitor of PDIA1 and PDIA3 proteins due to the presence of a chloroacetyl group that covalently modifies 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.
