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BY 4.0 license Open Access Published by De Gruyter Open Access December 31, 2021

Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection

  • Chilakamarti V. Ramana EMAIL logo and Bikul Das

Abstract

Type I interferons (IFN α/β) play a central role in innate immunity to respiratory viruses, including coronaviruses. In this study, transcription factor profiling in the transcriptome was used to gain novel insights into the role of inducible transcription factors in response to type I interferon signaling in immune cells and in lung epithelial cells after SARS-CoV-2 infection. Modeling the interferon-inducible transcription factor mRNA data in terms of distinct sub-networks based on biological functions such as antiviral response, immune modulation, and cell growth revealed enrichment of specific transcription factors in mouse and human immune cells. Interrogation of multiple microarray datasets revealed that SARS-CoV-2 induced high levels of IFN-beta and interferon-inducible transcription factor mRNA in human lung epithelial cells. Transcription factor mRNA of the three sub-networks were differentially regulated in human lung epithelial cell lines after SARS-CoV-2 infection and in COVID-19 patients. A subset of type I interferon-inducible transcription factors and inflammatory mediators were specifically enriched in the lungs and neutrophils of Covid-19 patients. The emerging complex picture of type I IFN transcriptional regulation consists of a rapid transcriptional switch mediated by the Jak-Stat cascade and a graded output of the inducible transcription factor activation that enables temporal regulation of gene expression.

MSC 2010: 00; 68; 92

References

[1] Stark, G. R., Kerr, I. M., Williams, B. R., et al. How cells respond to interferons. (1998). Annu Rev Biochem; 67, 227-264.10.1146/annurev.biochem.67.1.227Search in Google Scholar

[2] Park, A., Iwasaki, A. (2020). Type I and Type III Interferons - Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe, 27, 870-87810.1016/j.chom.2020.05.008Search in Google Scholar

[3] Platanias, L. (2005) Mechanisms of type- I- and Type-II-interferon-mediated signaling. Nature Rev Immunol, 5, 375-386.10.1038/nri1604Search in Google Scholar

[4] Weber, F., Haller, O. Viral suppression of the interferon system. (2007) Biochimie, 8, 836-842.10.1016/j.biochi.2007.01.005Search in Google Scholar

[5] Der, S. D., Zhou, A., Williams, B. R., Silverman, R. H. (1998). Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A; 95, 15623-15628.10.1073/pnas.95.26.15623Search in Google Scholar

[6] Stark, G. R., Darnell, J. E. Jr. The JAK-STAT pathway at twenty. Immunity, 36, 503-514.10.1016/j.immuni.2012.03.013Search in Google Scholar

[7] Waddell, S. J., Popper, S. J., Rubins, K. H, et al. (2010). Dissecting interferon-induced transcriptional programs in human peripheral blood cells. PLoS One, 5, e9753.10.1371/journal.pone.0009753Search in Google Scholar

[8] Mostafavi, S., Yoshida, H., Moodley, D., LeBoité, H., Rothamel, K., et. al. (2016). Immunological Genome Project Consortium. Parsing the Interferon Transcriptional Network and Its Disease Associations. Cell, 164, 564-578.10.1016/j.cell.2015.12.032Search in Google Scholar

[9] Gongora, R., Stephan, R. P., Schreiber, R. D., Cooper M. D. (2000) Stat-1 is not essential for inhibition of B lymphopoiesis by type I IFNs. J Immunol, 165, 2362-2366.10.4049/jimmunol.165.5.2362Search in Google Scholar

[10] Gongora, R., Stephan, R.P., Zhang, Z., Cooper, M. D. (2001) An essential role for Daxx in the inhibition of B lymphopoiesis by type I interferons. Immunity, 14, 727-737.10.1016/S1074-7613(01)00152-2Search in Google Scholar

[11] Meraz, M. A., White, J. M., Sheehan, K. C., Bach, E. A., et. al. (1996). Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell, 84, 431-442.10.1016/S0092-8674(00)81288-XSearch in Google Scholar

[12] Durbin, J. E., Hackenmiller, R., Simon, M. C., Levy, D. E. (1996). Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell, 84, 443-450.10.1016/S0092-8674(00)81289-1Search in Google Scholar

[13] Gil, M.P., Bohn, E., O’Guin, A. K., Ramana, C. V. et. al. (2001). Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A, 98, 6680-6685.10.1073/pnas.111163898Search in Google Scholar

[14] Wang, J., Schreiber, R. D, Campbell, I. L. (2002). STAT1 deficiency unexpectedly and markedly exacerbates the pathophysiological actions of IFN-alpha in the central nervous system. Proc Natl Acad Sci U S A, 99, 16209-16214.10.1073/pnas.252454799Search in Google Scholar

[15] Ousman, S. S., Wang, J., Campbell, I. L. (2005). Differential regulation of interferon regulatory factor (IRF)-7 and IRF-9 gene expression in the central nervous system during viral infection. J Virol, 79, 7514-7527.10.1128/JVI.79.12.7514-7527.2005Search in Google Scholar

[16] Kohlmeier, J. E., Woodland, D. L. (2009). Immunity to respiratory viruses. Annu Rev Immunol, 27, 61-82.10.1146/annurev.immunol.021908.132625Search in Google Scholar

[17] Ardain, A., Marakalala, M. J., Leslie, A. (2020). Tissue-resident innate immunity in the lung. Immunology, 159, 245-256.10.1111/imm.13143Search in Google Scholar

[18] Cui, J., Li, F., Shi Z. L. (2019). Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol, 17, 181-192.10.1038/s41579-018-0118-9Search in Google Scholar

[19] Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L. et. al. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579, 270–273.10.1038/s41586-020-2012-7Search in Google Scholar

[20] Huang, C., Wang, Y., Li, X., et. al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395, 497–506.10.1016/S0140-6736(20)30183-5Search in Google Scholar

[21] Zhang, Q., Bastard, P., Liu Z, Le Pen, J., Moncada-Velez M, et. al. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, 370, eabd457010.1126/science.abd4570Search in Google Scholar PubMed PubMed Central

[22] Bastard, P., Rosen, L. B., Zhang, Q., Michailidis, E., et. al. (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science, 370(6515)Search in Google Scholar

[23] Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A.D., et. al. (2020). Genetic mechanisms of critical illness in Covid-19. Nature. doi: 10.1038/s41586-020-03065-y.10.1038/s41586-020-03065-ySearch in Google Scholar PubMed

[24] Ramana, C. V. (2019). Insights into the signal transduction pathways of mouse lung type II cells revealed by Transcription Factor Profiling in the transcriptome. Genomics Inform, 17(1):e8.Search in Google Scholar

[25] Ramana, C. V. (2019). Insights into functional connectivity in mammalian signal transduction pathways by pairwise comparison of protein interaction partners of critical signaling hubs. bioRxiv DOI: ?10.1101/2019.12.30.89120010.1101/2019.12.30.891200Search in Google Scholar

[26] Ramana, C. V. (2020). Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses. bioRxiv, DOI: https://doi.org/10.1101/2020.08.14.24489710.1101/2020.08.14.244897Search in Google Scholar

[27] Blanco-Melo, D., Nilsson-Payant, B.E., Liu, W. C., Uhl, S., Hoagland D., (2020). Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell, 181, 1036-1045.e9.10.1016/j.cell.2020.04.026Search in Google Scholar PubMed PubMed Central

[28] Wilk A. J., Rustagi, A., Zhao N. Q., Roque, J., (2020). A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med, 7, 1070-1076.10.1038/s41591-020-0944-ySearch in Google Scholar PubMed PubMed Central

[29] Babicki, S, Arndt, D, Marcu, A., Liang, Y., et. al. (2016). Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res, 44(W1), W147-53.10.1093/nar/gkw419Search in Google Scholar PubMed PubMed Central

[30] Huang da, W., Sherman, B. T., Lempicki, R. A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc, 4(1), 44.10.1038/nprot.2008.211Search in Google Scholar PubMed

[31] Kanehisa, M., Furumichi, M., Tanabe, M., Sato, Y., Morishima, K. (2017). KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res, 45, D353-D361.10.1093/nar/gkw1092Search in Google Scholar PubMed PubMed Central

[32] Zhou, Y., Zhou, B., Pache, L., Chang, M., et. al. (2019). Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun, 10, 152310.1038/s41467-019-09234-6Search in Google Scholar PubMed PubMed Central

[33] Stark, C., Breitkreutz, B. J., Reguly, T., Boucher, L., Breitkreutz, A., Tyers, M. (2006). BIOGRID: a general repository for interaction datasets. Nucleic Acids Res, 34, D535-D539.10.1093/nar/gkj109Search in Google Scholar PubMed PubMed Central

[34] Szklarczyk, D., Morris, J.H., Cook, H., Kuhn, M., et. al. (2017). The STRING database in 2017. Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45:D362-D368.Search in Google Scholar

[35] Orii, N., Ganapathiraju, M. K. (2012). WIKI-PI: a web-server of annotated human protein-protein interactions to aid in discovery of protein function. PLoS One, 7, e49029.10.1371/journal.pone.0049029Search in Google Scholar PubMed PubMed Central

[36] Basler, C. F, García-Sastre, A. (2002). Viruses and the type I interferon antiviral system: induction and evasion. Int Rev Immunol, 2, 305-337.10.1080/08830180213277Search in Google Scholar PubMed

[37] Dupuis, S., Dargemont, C., Fieschi, C., Thomassin, N., et. al. (2001). Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science; 293, 300-303.10.1126/science.1061154Search in Google Scholar PubMed

[38] Mavrommatis, E., Fish, E. N., Platanias, L. C. (2013). The schlafen family of proteins and their regulation by interferons. J Interferon Cytokine Res, 33, 206-210.10.1089/jir.2012.0133Search in Google Scholar PubMed PubMed Central

[39] Andersson, R., Sandelin, A. (2020). Determinants of enhancer and promoter activities of regulatory elements. Nat Rev Genet, 21, 71-87.10.1038/s41576-019-0173-8Search in Google Scholar PubMed

[40] Papin, J. A., Hunter, T., Palsson, B. O, Subramaniam, S. (2005). Reconstruction of cellular signaling networks and analysis of their properties. Nat Rev Mol Cell Biol, 6, 99-111.10.1038/nrm1570Search in Google Scholar PubMed

[41] Korzus, E., Torchia, J., Rose, D.W., Xu, L., et. al. (1998). Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science, 279, 703-707.10.1126/science.279.5351.703Search in Google Scholar PubMed

[42] Zhang, J. J., Vinkemeier, U., Gu, W., Chakravarti, D., et. al. (1996). Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling. Proc Natl Acad Sci U S A, 93, 15092-15096.10.1073/pnas.93.26.15092Search in Google Scholar PubMed PubMed Central

[43] Zeng, L., Sun, Y., Xie, L., Wei, L., et. al. (2013). Construction of a novel oligonucleotide array-based transcription factor interaction assay platform and its uses for profiling STAT1 cofactors in mouse fibroblast cells. Proteomics, 13, 2377-2385.10.1002/pmic.201200521Search in Google Scholar PubMed

[44] Bulgakov, V. P, Tsitsishvili, GSh. (2013). Bioinformatics analysis of protein interaction networks: statistics, topologies, and meeting the standards of experimental biologists. Biochemistry (Mosc), 78, 1098-103.10.1134/S0006297913100039Search in Google Scholar PubMed

[45] Han, H., Cho, J. W, Lee, S., Yun, A., Kim, H., Bae, D., et. al. (2018). TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions Nucleic Acids Res, 46, D380-D386.10.1093/nar/gkx1013Search in Google Scholar PubMed PubMed Central

[46] Ashtiani, M., Salehzadeh-Yazdi, A., Razaghi-Moghadam, Z., Hennig, H., et. al. (2018). A systematic survey of centrality measures for protein-protein interaction networks. BMC Syst Biol, 12, 80.10.1186/s12918-018-0598-2Search in Google Scholar PubMed PubMed Central

[47] Kleinberg, J. (1999). Authoritative sources in a hyper-linked environment. Journal of the ACM; 46, 604-632.10.1145/324133.324140Search in Google Scholar

[48] Adelaja, A., Hoffmann, A. (2019). Signaling Crosstalk Mechanisms That May Fine-Tune Pathogen-Responsive NFκB. Front Immunol, 10, 433.10.3389/fimmu.2019.00433Search in Google Scholar PubMed PubMed Central

[49] Langevin, C., Aleksejeva, E., Passoni, G., Palha, N., Levraud, J P., Boudinot, P. (2013). The antiviral innate immune response in fish: evolution and conservation of the IFN system. J Mol Biol, 425, 4904-4920.10.1016/j.jmb.2013.09.033Search in Google Scholar PubMed

[50] Majzoub, K., Wrensch, F., Baumert, T. F. (2019). The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans. Viruses, 11, 758.10.3390/v11080758Search in Google Scholar PubMed PubMed Central

[51] Shaw, A. E., Hughes, J., Gu, Q., Behdenna, A., et. al. (2017). Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses. PLoS Biol, 15, e200408610.1371/journal.pbio.2004086Search in Google Scholar PubMed PubMed Central

[52] Zhang, B., Goraya, M. U., Chen, N., Xu, L.,et. al. (2020). Zinc Finger CCCH-Type Antiviral Protein 1 Restricts the Viral Replication by Positively Regulating Type I Interferon Response. Front Microbiol, 11, 1912.10.3389/fmicb.2020.01912Search in Google Scholar PubMed PubMed Central

[53] Dai, H., Yan, M., Li, Y. (2020). The zinc-finger protein ZCCHC2 suppresses retinoblastoma tumorigenesis by inhibiting HectH9-mediated K63-linked polyubiquitination and activation of c-Myc. Biochem Biophys Res Commun, 521, 533-538.10.1016/j.bbrc.2019.10.163Search in Google Scholar PubMed

[54] Ramana, C. V., Chatterjee-Kishore, M., Nguyen, H., Stark, G. R. Complex roles of Stat1 in regulating gene expression. Onco-gene, 19, 2619-2627.10.1038/sj.onc.1203525Search in Google Scholar

[55] Velichko, S., Wagner, T. C., Turkson, J., Jove, R., Croze, E. (2002). STAT3 activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c. Activation of multiple STATS proceeds through the redundant usage of two tyrosine residues. J Biol Chem, 277, 35635-35641.10.1074/jbc.M204578200Search in Google Scholar

[56] Watling D, Guschin D, Müller M, Silvennoinen O, et. al. (1993). Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature, 366, 166-170.10.1038/366166a0Search in Google Scholar

[57] Karaghiosoff, M., Neubauer, H., Lassnig, C., Kovarik, P., et. al. (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13, 549-560.10.1016/S1074-7613(00)00054-6Search in Google Scholar

[58] Yang CH, Murti A, Pfeffer LM. (1998). STAT3 complements defects in an interferon-resistant cell line: evidence for an essential role for STAT3 in interferon signaling and biological activities. Proc Natl Acad Sci U S A, 95, 5568-5572.10.1073/pnas.95.10.5568Search in Google Scholar PubMed PubMed Central

[59] Farrar, J. D., Smith, J. D., Murphy, T. L., Leung, S., Stark, G.R., Murphy, K. M. (2000). Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nat Immunol, 1, 65-69.10.1038/76932Search in Google Scholar PubMed

[60] Gadina, M., O’Shea, J. J., Biron, C. A. (2002). Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science, 297, 2063-2066.10.1126/science.1074900Search in Google Scholar PubMed

[61] Nguyen, K. B., Salazar-Mather, T. P, Dalod M. Y., Van Deusen, J. B., et. al. (2002). Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol, 169, 4279-4287.10.4049/jimmunol.169.8.4279Search in Google Scholar PubMed

[62] Matikainen, S., Sareneva, T., Ronni, T., Lehtonen, A., Koskinen, P. J, Julkunen, I. (1999). Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. Blood, 93, 1980-1991.10.1182/blood.V93.6.1980.406k20_1980_1991Search in Google Scholar

[63] Meinke, A., Barahmand-Pour, F., Wöhrl, S., Stoiber, D., Decker, T. (1996). Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons. Mol Cell Biol, 16, 6937-6944.10.1128/MCB.16.12.6937Search in Google Scholar PubMed PubMed Central

[64] Rani, M. R., Leaman, D. W., Han, Y., Leung, S., et. al. (1999). Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositide 3-kinase. J Biol Chem, 274, 32507-32511.10.1074/jbc.274.45.32507Search in Google Scholar

[65] Dupuis, S., Jouanguy, E., Al-Hajjar, S., Fieschi, C., et. al. (2003). Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet, 33, 388-391.10.1038/ng1097Search in Google Scholar

[66] Tsai, M. H, Pai, L. M, Lee, C. K. (2019). Fine-Tuning of Type I Interferon Response by STAT3. Front Immunol, 10, 144810.3389/fimmu.2019.01448Search in Google Scholar

[67] Uddin, S., Lekmine, F., Sassano, A., Rui, H., Fish, E.N., Platanias, L. C. (2003). Role of Stat5 in type I interferon-signaling and transcriptional regulation. Biochem Biophys Res Commun, 308, 325-330.10.1016/S0006-291X(03)01382-2Search in Google Scholar

[68] Pfeffer, L. M., Mullersman, J. E., Pfeffer, S. R., Murti, A., Shi, W., Yang. C. H. (1997). STAT3 as an adapter to couple phosphatidylinositol 3-kinase to the IFNAR1 chain of the type I interferon receptor. Science, 276, 1418-1420.10.1126/science.276.5317.1418Search in Google Scholar PubMed

[69] Wagner, T. C., Velichko, S., Vogel, D., Rani, M. R., et. al. (2002). Interferon signaling is dependent on specific tyrosines located within the intracellular domain of IFNAR2c. Expression of IFNAR2c tyrosine mutants in U5A cells. J Biol Chem, 277, 1493-1499.10.1074/jbc.M108928200Search in Google Scholar PubMed

[70] Arunachalam, P. S., Wimmers, F., Mok, C. K. P., Perera, R. A. P. M., Scott, M. S., et. al. (2020). Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science, 369, 1210-1220.10.1126/science.abc6261Search in Google Scholar PubMed PubMed Central

[71] Lucas, C., Wong, P., Klein, J., Castro, T. B. R., Silva, J., et. al. (2020). Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature, 584, 463-469.10.1038/s41586-020-2588-ySearch in Google Scholar PubMed PubMed Central

[72] Nienhold, R., Ciani, Y., Koelzer, V.H., Tzankov, A., et. al. (2020). Two distinct immunopathological profiles in autopsy lungs of COVID-19. Nat Commun, 11, 5086.10.1038/s41467-020-18854-2Search in Google Scholar PubMed PubMed Central

[73] Xu, L., Yoon, H., Zhao, M.Q., Liu, J., Ramana, C.V., Enelow. R. I. (2004). Cutting edge: pulmonary immunopathology mediated by antigen-specific expression of TNF-alpha by antiviral CD8+ T cells. J Immunol, 173, 721-725.10.4049/jimmunol.173.2.721Search in Google Scholar PubMed

[74] Ramana, C. V., DeBerge, M.P., Kumar, A., Alia. C.S., Durbin, J. E., Enelow, R. I. (2015). Inflammatory impact of IFN- γ in CD8+ T cell-mediated lung injury is mediated by both Stat1-dependent and – independent pathways. Am J Physiol Lung Cell Mol Physiol, 308, L650-L657.10.1152/ajplung.00360.2014Search in Google Scholar PubMed PubMed Central

[75] Verdecchia, P., Cavallini, C., Spanevello, A., Angeli, F. (2020). The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med, 76, 14-20.10.1016/j.ejim.2020.04.037Search in Google Scholar PubMed PubMed Central

[76] Imgenberg-Kreuz, J., Sandling, J. K., Björk, A., Nordlund, J., et. al. (2018). Transcription profiling of peripheral B cells in antibody-positive primary Sjögren’s syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature. Scand J Immunol, 87, e12662.10.1111/sji.12662Search in Google Scholar PubMed

[77] Imgenberg-Kreuz, J., Sandling, J. K., Almlöf, J. C, Nordlund J., et. al. (2016). Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren’s syndrome reveals regulatory effects at interferon-induced genes. Ann Rheum Dis, 75, 2029-2036.10.1136/annrheumdis-2015-208659Search in Google Scholar PubMed PubMed Central

[78] Silvin, A., Chapuis, N., Dunsmore, G., Goubet, A. G., et. al. (2020). Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19. Cell, 182, 1401-1418.e18.10.1016/j.cell.2020.08.002Search in Google Scholar PubMed PubMed Central

[79] Croft, M., Duan, W., Choi, H., Eun, S. Y, Madireddi, S., Mehta, A. (2012). TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol, 144-52.10.1016/j.it.2011.10.004Search in Google Scholar PubMed PubMed Central

[80] Xia, C., Braunstein, Z., Toomey, A. C., Zhong, J., Rao, X. (2018). S100 Proteins as an important regulator of macrophage inflammation. Front Immunol, 8, 1908.10.3389/fimmu.2017.01908Search in Google Scholar PubMed PubMed Central

[81] Wrobleski, S. T., Moslin, R., Lin, S., Zhang, Y., et. al. (2019). Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165. J Med Chem, 62, 8973-8995.10.1021/acs.jmedchem.9b00444Search in Google Scholar PubMed

[82] Norman, P. (2012). Selective JAK1 inhibitor and selective Tyk2 inhibitor patents. Expert Opin Ther Pat, 22, 1233-1249.10.1517/13543776.2012.723693Search in Google Scholar PubMed

Received: 2021-07-21
Accepted: 2021-12-13
Published Online: 2021-12-31

© 2021 Chilakamarti V. Ramana et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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