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      Interferons at age 50: past, current and future impact on biomedicine

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          Key Points

          • On the 50th anniversary of the discovery of interferon (IFN), we offer a perspective from more than 100,000 published papers, highlighting initial pivotal discoveries and more recent findings of conceptual importance. This covers the mechanisms of IFN induction, the cellular actions of IFN and IFN-stimulated genes (ISGs), and human therapeutic applications.

          • The synthesis of IFNs requires stimulation by viruses or microbial products binding to Toll-like receptors, or chemical inducers. The development of small-molecule modulators is still in its infancy, but the delineation of the responsible signalling pathways has identified many target proteins.

          • IFNs constitute a large protein family that can be subdivided into three types, binding to different receptors. These receptors initiate signalling by activating a complex signalling cascade regulated at many levels, resulting in a diverse pattern of ISG induction.

          • ISGs are a diverse group of more than 300 genes, which can have direct antiviral and antitumour functions. These are attractive targets for high-throughput screening for the identification of new modulators of the IFN system.

          • IFNs were initially investigated for their potential as antivirals, and are now commonly used in anti-HBV (hepatitis B virus) and anti-HCV (hepatitis C virus) therapy. They might also have prophylactic or therapeutic effectiveness in SARS (severe acute respiratory syndrome), influenza or another virus pandemic.

          • The first FDA approval of an IFN was, however, not for virus infection but for cancer. The mechanisms of antitumour action are incompletely understood. Aberrations of the IFN system are also emerging as important contributors to cancer development.

          • IFNs also proved effectiveness in relapsing, remitting multiple sclerosis. It is now common practice to initiate IFN-β treatment at the time of diagnosis.

          • Because of the effectiveness of IFNs in limiting virus replication, reducing tumour cell mass, controlling disease symptoms and prolonging survival, market sales of IFNs approach US$4 billion. As all the effects of IFNs are mediated through ISGs, understanding of the function of these genes might lead to more efficacious antiviral and anti-cancer drugs.

          Abstract

          Interferons (IFNs) provide fundamental cellular defence mechanisms against viral infections and cancer. On the 50th anniversary of the discovery of IFNs, the authors provide a comprehensive overview of IFN biology, human therapeutic applications and potential drug targets within the IFN system.

          Abstract

          The family of interferon (IFN) proteins has now more than reached the potential envisioned by early discovering virologists: IFNs are not only antivirals with a spectrum of clinical effectiveness against both RNA and DNA viruses, but are also the prototypic biological response modifiers for oncology, and show effectiveness in suppressing manifestations of multiple sclerosis. Studies of IFNs have resulted in fundamental insights into cellular signalling mechanisms, gene transcription and innate and acquired immunity. Further elucidation of the multitude of IFN-induced genes, as well as drug development strategies targeting IFN production via the activation of the Toll-like receptors (TLRs), will almost certainly lead to newer and more efficacious therapeutics. Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.

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          Most cited references231

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          RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

          Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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            Antiviral actions of interferons.

            C Samuel (2001)
            Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2',5'-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2'-5'-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-alpha, IFN-beta, and IFN-gamma, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2',5'-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system reagents, both in cell culture and in whole animals, continues to provide important contributions to our understanding of the virus-host interaction and cellular antiviral response.
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              Angiogenesis: an organizing principle for drug discovery?

              Angiogenesis--the process of new blood-vessel growth--has an essential role in development, reproduction and repair. However, pathological angiogenesis occurs not only in tumour formation, but also in a range of non-neoplastic diseases that could be classed together as 'angiogenesis-dependent diseases'. By viewing the process of angiogenesis as an 'organizing principle' in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained. This has important consequences for the clinical use of angiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but possibly also for developing therapeutic approaches for various diseases that are otherwise unrelated to each other.
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                Author and article information

                Contributors
                bordene@ccf.org
                uze@univ-montp2.fr
                Journal
                Nat Rev Drug Discov
                Nat Rev Drug Discov
                Nature Reviews. Drug Discovery
                Nature Publishing Group UK (London )
                1474-1776
                1474-1784
                2007
                : 6
                : 12
                : 975-990
                Affiliations
                [1 ]Taussig Cancer Center, Case Comprehensive Cancer Center, Mellen Center for Multiple Sclerosis, and Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, 44195 Ohio USA
                [2 ]GRID grid.464150.2, ISNI 0000 0004 0383 9805, CNRS UMR 5235, Place Eugene Bataillon, ; Montpellier, Cedex 5 FR34095 France
                [3 ]GRID grid.4868.2, ISNI 0000 0001 2171 1133, Institute of Cell and Molecular Science, Queen Mary's School of Medicine, ; 4 Newark Street, London, E1 4AT UK
                Article
                BFnrd2422
                10.1038/nrd2422
                7097588
                18049472
                43e89cc6-0df2-48af-bc20-1963969ac9c6
                © Nature Publishing Group 2007

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2007

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