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1.
Sci Rep ; 14(1): 5758, 2024 03 08.
Article in English | MEDLINE | ID: mdl-38459035

ABSTRACT

Two types of immunity, humoral and cellular, offer protection against COVID. Humoral protection, contributed by circulating neutralizing antibodies, can provide immediate protection but decays more quickly than cellular immunity and can lose effectiveness in the face of mutation and drift in the SARS-CoV-2 spike protein. Therefore, population-level seroprevalence surveys used to estimate population-level immunity may underestimate the degree to which a population is protected against COVID. In early 2021, before India began its vaccination campaign, we tested for humoral and cellular immunity to SARS-Cov-2 in representative samples of slum and non-slum populations in Bangalore, India. We found that 29.7% of samples (unweighted) had IgG antibodies to the spike protein and 15.5% had neutralizing antibodies, but at up to 46% showed evidence of cellular immunity. We also find that prevalence of cellular immunity is significantly higher in slums than in non-slums. These findings suggest (1) that a significantly larger proportion of the population in Bangalore, India, had cellular immunity to SARS-CoV-2 than had humoral immunity, as measured by serological surveys, and (2) that low socio-economic status communities display higher frequency of cellular immunity, likely because of greater exposure to infection due to population density.


Subject(s)
COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , India/epidemiology , COVID-19/epidemiology , Seroepidemiologic Studies , Immunity, Cellular , Antibodies, Neutralizing , Immunity, Humoral , Antibodies, Viral , Vaccination
2.
Indian J Med Microbiol ; 41: 45-52, 2023.
Article in English | MEDLINE | ID: mdl-36870749

ABSTRACT

PURPOSE: The study aims to isolate and understand cytopathogenesis, ultrastructure, genomic characteristics and phylogenetic analysis of SARS-CoV-2 virus of B.1.210 lineage, that circulated in India during first wave of the pandemic. METHODS: Clinical specimen from an interstate traveller from Maharashtra to Karnataka, in May 2020, who was positive by RT PCR for SARS-CoV-2 infection was subjected to virus isolation and Whole Genome Sequencing. Vero cells were used to study cytopathogenesis and ultrastructural features by Transmission Electron Microscopy (TEM). Phylogenetic analysis of the whole genome sequences of several SARS-CoV-2 variants downloaded from GISAID was performed in comparison with the B.1.210 variant identified in this study. RESULTS: The virus was isolated in Vero cells and identified by immunofluorescence assay and RT PCR. The growth kinetics in infected Vero cells revealed a peak viral titre at 24 â€‹h post-infection. Ultrastructural studies revealed distinct morphological changes with accumulation of membrane-bound vesicles containing pleomorphic virions in the cytoplasm, with single or multiple intranuclear filamentous inclusions and dilated rough endoplasmic reticulum with viral particles. Whole genome sequence of the clinical specimen as well as the isolated virus revealed the virus to be of lineage B.1.210 with the D614G mutation in the spike protein. Phylogenetic analysis of the whole genome sequence in comparison with other variants reported globally revealed that the isolated SARS-CoV-2 virus of lineage B.1.210 is closely related to the original Wuhan virus reference sequence. CONCLUSIONS: The SARS-CoV-2 variant B.1.210 virus isolated here showed ultrastructural features and cytopathogenesis similar to that of the virus reported during early phase of pandemic. Phylogenetic analysis showed that the isolated virus is closely related to the original Wuhan virus, thereby suggesting that the SARS-CoV-2 lineage B.1.210 that was circulating in India during the early phase of pandemic is likely to have evolved from the original Wuhan strain.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Chlorocebus aethiops , Animals , Pandemics , Phylogeny , Vero Cells , India , Genomics
3.
J Med Chem ; 59(7): 3098-111, 2016 Apr 14.
Article in English | MEDLINE | ID: mdl-26987013

ABSTRACT

Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.


Subject(s)
Inflammatory Bowel Diseases/drug therapy , Isoindoles/chemistry , Receptors, CCR/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Chemistry Techniques, Synthetic , Chemotaxis/drug effects , Colitis/chemically induced , Colitis/drug therapy , Disease Models, Animal , Humans , Isoindoles/administration & dosage , Isoindoles/pharmacokinetics , Male , Mice, Inbred C57BL , Receptors, CCR/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics
4.
Naunyn Schmiedebergs Arch Pharmacol ; 384(6): 555-63, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21947231

ABSTRACT

ß-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of ß-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M(3)-sparing muscarinic agonist, providing selective M(2) stimulation in rat bladder, and THRX-182087 as a highly M(2)-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M(2) or M(3) receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M(2)-selective stimulation partly mimicked this attenuation, indicating that both M(2) and M(3) receptors are involved. During M(3)-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M(2) and M(3) receptors contribute to attenuation of ß-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M(3) component of this attenuation differs from that mediating direct contractile effects of M(3) receptors.


Subject(s)
Muscle Relaxation/drug effects , Receptor, Muscarinic M2/drug effects , Receptor, Muscarinic M3/drug effects , Urinary Bladder/drug effects , Adrenergic beta-Agonists/pharmacology , Animals , Carbachol/pharmacology , Isoproterenol/pharmacology , Male , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Rats , Rats, Wistar , Receptor, Muscarinic M2/metabolism , Receptor, Muscarinic M3/metabolism , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta/metabolism , Signal Transduction/drug effects , Urinary Bladder/metabolism
5.
Bioorg Med Chem Lett ; 16(3): 746-9, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16321528

ABSTRACT

The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described.


Subject(s)
Calcium Channels/metabolism , Combinatorial Chemistry Techniques/methods , Ion Channel Gating , Protein Subunits/metabolism , Calcium Channels/chemistry , Calcium Channels/drug effects , Humans , Ligands , Protein Subunits/chemistry , Solutions/chemistry , Structure-Activity Relationship
6.
J Biol Chem ; 280(2): 1257-63, 2005 Jan 14.
Article in English | MEDLINE | ID: mdl-15504725

ABSTRACT

Expression of functional, recombinant alpha7 nicotinic acetylcholine receptors in several mammalian cell types, including HEK293 cells, has been problematic. We have isolated the recently described human ric-3 cDNA and co-expressed it in Xenopus oocytes and HEK293 cells with the human nicotinic acetylcholine receptor alpha7 subunit. In addition to confirming the previously reported effect on alpha7 receptor expression in Xenopus oocytes we demonstrate that ric-3 promotes the formation of functional alpha7 receptors in mammalian cells, as determined by whole cell patch clamp recording and surface alpha-bungarotoxin binding. Upon application of 1 mm nicotine, currents were undetectable in HEK293 cells expressing only the alpha7 subunit. In contrast, co-expression of alpha7 and ric-3 cDNAs resulted in currents that averaged 42 pA/pF with kinetics similar to those observed in cells expressing endogenous alpha7 receptors. Immunoprecipitation studies demonstrate that alpha7 and ric-3 proteins co-associate. Additionally, cell surface labeling with biotin revealed the presence of alpha7 protein on the plasma membrane of cells lacking ric-3, but surface alpha-bungarotoxin staining was only observed in cells co-expressing ric-3. Thus, ric-3 appears to be necessary for proper folding and/or assembly of alpha7 receptors in HEK293 cells.


Subject(s)
Proteins/metabolism , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Animals , Blotting, Western , Bungarotoxins/metabolism , Cell Line , Electric Conductivity , Gene Expression Regulation , Humans , Immunoprecipitation , Intracellular Signaling Peptides and Proteins , Neurons/metabolism , Oocytes/metabolism , Protein Binding , Protein Subunits/analysis , Protein Subunits/genetics , Protein Subunits/metabolism , Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Receptors, Nicotinic/analysis , Xenopus , alpha7 Nicotinic Acetylcholine Receptor
7.
Bioorg Med Chem Lett ; 14(10): 2463-7, 2004 May 17.
Article in English | MEDLINE | ID: mdl-15109633

ABSTRACT

We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha 2 delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC(50)=15 nM) and (S)-22 (IC(50)=30 nM). A potent and selective radioligand, [(3)H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.


Subject(s)
Calcium Channel Blockers/chemical synthesis , Calcium Channels/metabolism , Phthalazines/pharmacology , Amines/metabolism , Analgesics/chemical synthesis , Analgesics/pharmacology , Binding Sites , Calcium Channel Blockers/pharmacology , Cyclohexanecarboxylic Acids/metabolism , Gabapentin , Humans , Inhibitory Concentration 50 , Ligands , Phthalazines/chemical synthesis , Radioligand Assay , Structure-Activity Relationship , gamma-Aminobutyric Acid/metabolism
8.
Bioorg Med Chem Lett ; 14(9): 2031-4, 2004 May 03.
Article in English | MEDLINE | ID: mdl-15080973

ABSTRACT

A novel class of 2H-pyrrolo[3,4-c]pyridazine ligands of the alpha (2) delta subunit of voltage-gated calcium channels is described. Compound 4a with high affinity toward alpha (2) delta was identified through structure-activity relationship studies of the lead compound. Tritiated ligand [(3)H]-4b was synthesized to demonstrate that this ligand binds to the same site as Gabapentin toward alpha (2) delta subunit of voltage-gated calcium channels.


Subject(s)
Calcium Channels/drug effects , Ion Channel Gating , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Drug Evaluation, Preclinical , Ligands , Pyridazines/chemistry , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 14(8): 1913-6, 2004 Apr 19.
Article in English | MEDLINE | ID: mdl-15050626

ABSTRACT

A series of N-acridin-9-yl-butane-1,4-diamines were found to be high-affinity ligands of the alpha(2)delta subunit of voltage gated calcium channels. The SAR studies of butane-1,4-diamine side chain resulted in the identification of compound 10 (IC(50)=9 nM), which is more potent than gabapentin (IC(50)=27 nM). Partial saturation of the acridine ring was also pursued and provided a compound with higher binding affinity than 1.


Subject(s)
Amines , Calcium Channels/physiology , Cyclohexanecarboxylic Acids , Diamines/chemistry , Diamines/pharmacology , Protein Subunits/physiology , gamma-Aminobutyric Acid , Acetates/pharmacology , Binding, Competitive/drug effects , Calcium Channels/drug effects , Diamines/chemical synthesis , Gabapentin , Ligands , Molecular Structure , Protein Binding/drug effects , Protein Binding/physiology , Protein Subunits/drug effects , Structure-Activity Relationship
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