Publications by authors named "G Kumaravel"

31 Publications

Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2.

Indian J Pediatr 2021 Nov 24. Epub 2021 Nov 24.

Department of Pediatric Cardiology, Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India.

Objectives: To know the clinical presentation and outcome of children with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV- 2 (PIMS-TS) at a pediatric tertiary care center in Chennai.

Methods: Clinical and biochemical parameters of 65 children with PIMS-TS treated between July and October 2020 were studied. All children had their COVID RT-PCR and IgG COVID antibodies tests done.

Results: Mean age of the study group was 5.65 ± 3.68 y. Fever with red eyes, rash, vomiting, abdominal pain, and shock were common presenting features. Sixty percent of the study group had Kawasaki/incomplete Kawasaki features. Sixty-seven percent of the study group had coronary dilatation, 41% presented with shock, and 25% had left ventricular dysfunction. Coronary aneurysms were documented in 58% of the study group (z score more than 2.5). Respiratory presentation with pneumonia was seen in 10%. Four children presented with acute abdomen. Acute kidney injury, acute liver failure, hemolysis, pancytopenia, macrophage activation syndrome, encephalopathy, and multiorgan dysfunction syndrome (MODS) were other features. Forty-three percent required noninvasive oxygen support and 15.4% required mechanical ventilation. Intravenous immunoglobulin (73.8%) and methylprednisolone (49.8%) were used for therapy. Mortality in the study was 6%, which was due to MODS.

Conclusions: Acute febrile illness with mucocutaneous and gastrointestinal manifestations should have PIMS-TS as a possible differential diagnosis and needs evaluation with inflammatory markers and SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1007/s12098-021-03954-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611247PMC
November 2021

Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546.

ACS Med Chem Lett 2021 Jul 14;12(7):1124-1129. Epub 2021 Jun 14.

Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.

Autotaxin (ATX) is a lysophospholipase D that is the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from a conditioned medium of melanoma cells, later it was discovered to play a critical role in vascular and neuronal development. ATX has also been implicated in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as neurological diseases such as multiple sclerosis, Alzheimer's disease, and neuropathic pain. As ATX and LPA levels are increased upon neuronal injury, a selective ATX inhibitor could provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274069PMC
July 2021

PEARL-seq: A Photoaffinity Platform for the Analysis of Small Molecule-RNA Interactions.

ACS Chem Biol 2020 09 17;15(9):2374-2381. Epub 2020 Aug 17.

Arrakis Therapeutics, 830 Winter Street, Waltham, Massachusetts, United States.

RNA is emerging as a valuable target for the development of novel therapeutic agents. The rational design of RNA-targeting small molecules, however, has been hampered by the relative lack of methods for the analysis of small molecule-RNA interactions. Here, we present our efforts to develop such a platform using photoaffinity labeling. This technique, termed hotoaffinity vluation of NA igation-uencing (PEARL-seq), enables the rapid identification of small molecule binding locations within their RNA targets and can provide information on ligand selectivity across multiple different RNAs. These data, when supplemented with small molecule SAR data and RNA probing data enable the construction of a computational model of the RNA-ligand structure, thereby enabling the rational design of novel RNA-targeted ligands.
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http://dx.doi.org/10.1021/acschembio.0c00357DOI Listing
September 2020

Exploring the DNA interactions, FGF growth receptor interaction and biological screening of metal(II) complexes of NNN donor ligand derived from 2‑(aminomethyl)benzimidazole.

Int J Biol Macromol 2019 Apr 20;126:1303-1317. Epub 2018 Sep 20.

Research Department of Chemistry, VHNSN College (Autonomous), Virudhunagar 626 001, India. Electronic address:

This work deals with a series of biologically important novel transition metal(II) Schiff base chelates containing terpyridine. Benzimidazole, a moiety found in broad spectrum of drugs is espoused in a Schiff base ligand system. Eight such metal(II) complexes are designed, synthesized and characterized. An octahedral geometry has been envisaged for all the complexes. DNA-binding behaviours are studied by absorption titration, electrochemical, viscosity, fluorescence and circular dichroism methods. The DNA cleavage ability is also evaluated by agarose gel electrophoresis method. These studies reveal that the complexes show an intercalative mode of binding to CT-DNA and also effectively cleave the supercoiled pBR322 DNA. The molecular docking studies of the complexes against FGF growth receptors indicate that they bind through electrostatic, van der Waals, hydrogen bonding and π-π interactions. The ligand and its complexes are screened for in vitro antimicrobial activities against a few microorganisms. The data exhibit that they are better antimicrobial agents than the ligand. The cytotoxic activity of the complexes is probed in four cell lines wherein the complex 5 has good cytotoxic activity and is partial to MCF-7 cell line which is comparable with the cisplatin drug which can be attributed to the presence of planar terpyridine co-ligand.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.09.116DOI Listing
April 2019

Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction.

Sci Rep 2018 09 7;8(1):13438. Epub 2018 Sep 7.

Biotherapeutics and Medicinal Sciences, Biogen Inc, Cambridge, Massachusetts, USA.

Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory. Lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring the PICK1-GluA2 interaction as a therapeutic target for neurological diseases. Here, we report the discovery of PICK1 small molecule inhibitors using a structure-based drug design strategy. The inhibitors stabilized surface GluA2, reduced Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and blocked long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.
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http://dx.doi.org/10.1038/s41598-018-31680-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128908PMC
September 2018
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