Publications by authors named "Ingrid C Choong"

12 Publications

  • Page 1 of 1

A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.

Nature 2020 10 27;586(7830):560-566. Epub 2020 Aug 27.

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2). Here we used reverse genetics to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-19.
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http://dx.doi.org/10.1038/s41586-020-2708-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034761PMC
October 2020

A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures.

bioRxiv 2020 May 7. Epub 2020 May 7.

Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the S and mACE2 binding interface resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells , and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of IFN lambda-1a treatment in human COVID-19 infections.
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http://dx.doi.org/10.1101/2020.05.06.081497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263553PMC
May 2020

Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors.

Bioorg Med Chem Lett 2010 Jul 25;20(14):4060-4. Epub 2010 May 25.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50)=430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).
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http://dx.doi.org/10.1016/j.bmcl.2010.05.086DOI Listing
July 2010

Modifications of the isonipecotic acid fragment of SNS-032: analogs with improved permeability and lower efflux ratio.

Bioorg Med Chem Lett 2008 Dec 2;18(23):6236-9. Epub 2008 Oct 2.

Sunesis Pharmaceuticals, 341 Oyster Point Blvd, South San Francisco, CA 94080, USA.

Modifications of the isonipecotic acid fragment of SNS-032 results in analogs which are more permeable and lower effluxed than SNS-032. The enantiomerically pure synthesis and the in vivo profile of analog 20 is described.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.099DOI Listing
December 2008

A diaminocyclohexyl analog of SNS-032 with improved permeability and bioavailability properties.

Bioorg Med Chem Lett 2008 Nov 24;18(21):5763-5. Epub 2008 Sep 24.

Medicinal Chemistry, Sunesis Pharmaceuticals, South San Francisco, CA 94080, USA.

The identification of a selective CDK2, 7, 9 inhibitor 4 with improved permeability is described. Compound 4 exhibits comparable CDK selectivity profile to SNS-032, but shows improved permeability and higher bioavailability in mice.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.073DOI Listing
November 2008

Design and synthesis of 2-amino-pyrazolopyridines as Polo-like kinase 1 inhibitors.

Bioorg Med Chem Lett 2008 Oct 29;18(20):5648-52. Epub 2008 Aug 29.

Department of Biology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard Suite 400, South San Francisco, CA 94080, USA.

A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.095DOI Listing
October 2008

Small-molecule inhibition of TNF-alpha.

Science 2005 Nov;310(5750):1022-5

Sunesis Pharmaceuticals, Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.
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http://dx.doi.org/10.1126/science.1116304DOI Listing
November 2005

Identification of potent and novel small-molecule inhibitors of caspase-3.

Bioorg Med Chem Lett 2003 Nov;13(21):3651-5

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

The design and synthesis of a series of novel, reversible, small molecule inhibitors of caspase-3 are described.
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http://dx.doi.org/10.1016/j.bmcl.2003.08.024DOI Listing
November 2003

In situ assembly of enzyme inhibitors using extended tethering.

Nat Biotechnol 2003 Mar 3;21(3):308-14. Epub 2003 Feb 3.

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
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http://dx.doi.org/10.1038/nbt786DOI Listing
March 2003

Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.

J Med Chem 2002 Nov;45(23):5005-22

Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.

The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
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http://dx.doi.org/10.1021/jm020230jDOI Listing
November 2002

Synthesis of Alkoxylamines by Alkoxide Amination with 3,3'-Di-tert-butyloxaziridine.

J Org Chem 1999 Sep;64(18):6528-6529

Department of Chemistry, University of California, Berkeley, California 94720.

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http://dx.doi.org/10.1021/jo990490hDOI Listing
September 1999
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