Delving into the Latest Updates on iOWH-032 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CFTR

Mechanism

CFTR inhibitors(Cystic fibrosis transmembrane conductance regulator inhibitors)

Therapeutic Areas

Infectious DiseasesOther Diseases

Active Indication-

Inactive Indication

Acute diarrheaCholeraDiarrhea+ [1]

Originator Organization

Program for Appropriate Technology in Health

Active Organization-

Inactive Organization

Program for Appropriate Technology in Health

PATH Drug Solutions

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC22H15Br2N3O4

InChIKeyDSFNLJXHXBIKDS-UHFFFAOYSA-N

CAS Registry1191252-49-9

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains a clinically untapped target. Nsp13 is a helicase responsible for unwinding double-stranded RNA during viral replication and is essential for propagation. Like other helicases, Nsp13 has two active sites: a nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) and a nucleic acid binding channel that unwinds double-stranded RNA or DNA. Targeting viral helicases with small molecules, as well as the identification of ligand binding pockets, have been ongoing challenges, partly due to the flexible nature of these proteins. Here, we use a virtual screen to identify ligands of Nsp13 from a collection of clinically used drugs. We find that a known ion channel inhibitor, IOWH-032, inhibits the dual ATPase and helicase activities of SARS-CoV-2 Nsp13 at low micromolar concentrations. Kinetic and binding assays, along with computational and mutational analyses, indicate that IOWH-032 interacts with the RNA binding interface, leading to displacement of nucleic acid substrate, but not bound ATP. Evaluation of IOWH-032 with microbial helicases from other superfamilies reveals that it is selective for coronavirus Nsp13. Furthermore, it remains active against mutants representative of observed SARS-CoV-2 variants. Overall, this work provides a new inhibitor for Nsp13 and provides a rationale for a recent observation that IOWH-032 lowers SARS-CoV-2 viral loads in human cells, setting the stage for the discovery of other potent viral helicase modulators.

01 Aug 2016·American Journal of Physiology-Lung Cellular and Molecular PhysiologyQ2 · MEDICINE

Potentiators exert distinct effects on human, murine, andXenopusCFTR

Q2 · MEDICINE

Article

Author: Senderowitz, Hanoch ; Infield, Daniel T. ; Imhoff, Barry R. ; Cui, Guiying ; Khazanov, Netaly ; Stauffer, Brandon B. ; McCarty, Nael A.

VX-770 (Ivacaftor) has been approved for clinical usage in cystic fibrosis patients with several CFTR mutations. Yet the binding site(s) on CFTR for this compound and other small molecule potentiators are unknown. We hypothesize that insight into this question could be gained by comparing the effect of potentiators on CFTR channels from different origins, e.g., human, mouse, and Xenopus (frog). In the present study, we combined this comparative molecular pharmacology approach with that of computer-aided drug discovery to identify and characterize new potentiators of CFTR and to explore possible mechanism of action. Our results demonstrate that 1) VX-770, NPPB, GlyH-101, P1, P2, and P3 all exhibited ortholog-specific behavior in that they potentiated hCFTR, mCFTR, and xCFTR with different efficacies; 2) P1, P2, and P3 potentiated hCFTR in excised macropatches in a manner dependent on the degree of PKA-mediated stimulation; 3) P1 and P2 did not have additive effects, suggesting that these compounds might share binding sites. Also 4) using a pharmacophore modeling approach, we identified three new potentiators (IOWH-032, OSSK-2, and OSSK-3) that have structures similar to GlyH-101 and that also exhibit ortholog-specific potentiation of CFTR. These could potentially serve as lead compounds for development of new drugs for the treatment of cystic fibrosis. The ortholog-specific behavior of these compounds suggest that a comparative pharmacology approach, using cross-ortholog chimeras, may be useful for identification of binding sites on human CFTR.

01 Aug 2011·Future Medicinal ChemistryQ4 · MEDICINE

Developing Novel Antisecretory Drugs to Treat Infectious Diarrhea

Q4 · MEDICINE

Review

Author: Tue Nguyen ; Eugenio L de Hostos ; Robert K M Choy

Diarrhea, a disease of poverty and poor sanitation, kills an estimated two million children each year. Oral rehydration therapy is a very simple and inexpensive treatment that has significantly reduced mortality from secretory diarrhea caused by rotavirus, cholera and enterotoxigenic Escherichia coli. The efficacy and adoption of oral rehydration therapy would be enhanced by a drug that reduces fluid loss associated with these diseases and alleviates disease symptoms. Secretion and absorption by the intestine offer a number of potential drug targets to reduce fluid loss. Among these, the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most attractive because it is the primary driver of secretion in cases of diarrhea caused by enterotoxigenic bacteria. CFTR can be inhibited by both natural products and synthetic small molecules. iOWH032 is a synthetic CFTR inhibitor that has recently entered clinical trials for this indication.

100 Deals associated with iOWH-032

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12959

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute diarrhea	Phase 2	BD	Program for Appropriate Technology in Health	01 Jun 2014
Cholera	Phase 2	BD	Program for Appropriate Technology in Health	01 Jun 2014
Cholera	Phase 2	BD	Program for Appropriate Technology in Health	01 Jun 2014
Secretory diarrhea	Phase 2	BD	Program for Appropriate Technology in Health	01 Jun 2014
Diarrhea	Phase 2	US	PATH Drug Solutions	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04150250 (Pubmed \| PLoS Negl Trop Dis)	Phase 2	Cholera	47	iOWH032	(kecvintgck) = smiousurye cgmpndtqrb (fhgsppzkau, 8.9 - 58.3)	Negative	18 Nov 2021
				Placebo	(kecvintgck) = tzxogpqtzr cgmpndtqrb (fhgsppzkau, 15.8 - 48.2)
NCT04150250 (CAST, CTgov)	Phase 2	Cholera	47	Antibiotics+iOWH032 (iOWH032)	wbqwnvaexa(oiomrlpkjk) = mkkmccgarj agboahzkfe (yyellxmsme, gpvykmnplj - zbqehqenps) View more	-	25 Mar 2021
				Placebo (Placebo)	wbqwnvaexa(oiomrlpkjk) = rofnjljqsx agboahzkfe (yyellxmsme, wpyvgyjsfg - rpxwnllizk) View more