Inhibition of protein disulfide-isomerase A3
Inventors
Rossignol, Jean-Francois • Santoro, Maria Gabriella
Assignees
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Publication Number
US-11173149-B2
Publication Date
2021-11-16
Expiration Date
Abstract
Provided are methods of treating a disease or condition associated with an increased level of expression of a protein disulfide-isomerase A3 (PDIA3) by administering to a subject with an increased level of expression of PDIA3 a PDIA3-inhibiting effective amount of a thiazolide compound, such as nitazoxanide or tizoxanide. Also provided are methods of screening for therapeutic agents based on PDIA3 inhibition.
Core Innovation
The invention describes inhibiting protein disulfide-isomerase A3 (PDIA3) using thiazolide compounds, including nitazoxanide (NTZ) and tizoxanide (TIZ), to treat diseases or conditions associated with increased PDIA3 expression. The disclosed therapeutic approach is framed as administering a protein disulfide-isomerase A3-inhibiting effective amount of a pharmaceutical composition comprising at least one thiazolide compound.
The disclosure emphasizes selective PDIA3 inhibition, including preferential inhibition of PDIA3 over other protein disulfide isomerases, such as PDIA1. A screening concept is described in which PDIA3 IC50 is used as an efficacy correlator for evaluating the thiazolide compounds.
Mechanistic and experimental evidence is provided in influenza models. NTZ is reported to affect PDIA3-hemagglutinin interactions as assessed by proximity ligation assay, and TIZ is reported to inhibit recombinant PDIA3 disulfide reductase activity in vitro with dose and kinetic effects. The disclosure further reports that PDIA3 silencing or NTZ treatment reduces hemagglutinin maturation and transport to the plasma membrane and decreases viral progeny in A549/MDCK cells.
Claims Coverage
The independent claim covers a method of treating a disease or condition associated with increased PDIA3 expression by administering an effective amount of a pharmaceutical composition comprising thiazolide compounds that selectively inhibit PDIA3 over other protein disulfide isomerases, limited to liver fibrosis or renal fibrosis. Dependent claims refine the selectable thiazolide compounds, salt forms, formulation combinations, and specific narrowing to renal fibrosis and/or human subjects.
Treating increased PDIA3 expression with a thiazolide pharmaceutical composition
Administering to a subject in need thereof a protein disulfide-isomerase A3-inhibiting effective amount of a pharmaceutical composition comprising at least one thiazolide compound for treating a disease or condition associated with an increased level of expression of protein disulfide-isomerase A3.
Selective inhibition of PDIA3 over other protein disulfide isomerases
Using the at least one thiazolide compound such that it inhibits protein disulfide isomerase A3 more than it inhibits other protein disulfide isomerases.
Thiazolide compound selection: nitazoxanide and/or tizoxanide
The at least one thiazolide compound comprises nitazoxanide or a pharmaceutically acceptable salt thereof, tizoxanide or a pharmaceutically acceptable salt thereof, or a combination thereof.
Disease indication limited to liver fibrosis or renal fibrosis
Wherein the disease or condition is a liver fibrosis or a renal fibrosis.
Overall claim coverage centers on administering PDIA3-inhibiting thiazolide compounds, including nitazoxanide and/or tizoxanide and pharmaceutically acceptable salts, with selective PDIA3 inhibition relative to other protein disulfide isomerases, for treating liver fibrosis or renal fibrosis associated with increased PDIA3 expression.
Stated Advantages
Selective inhibition of protein disulfide isomerase A3 more than other protein disulfide isomerases.
Use of PDIA3 IC50 as an efficacy correlator for screening.
Documented Applications
Treating liver fibrosis and renal fibrosis associated with increased PDIA3 expression.
Influenza model use showing effects on PDIA3-hemagglutinin interactions, PDIA3 disulfide reductase activity, hemagglutinin maturation and transport to the plasma membrane, and viral progeny reduction in A549/MDCK cells.
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