Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as (SARS-CoV) 3CLpro inhibitors...

Bioorganic & Medicinal Chemistry Letters
Volume 23, Issue 22, 15 November 2013, Pages 6172-6177

Mark Turlington, Aspen Chun, Sakshi Tomar, Aimee Eggler, Valerie Grum-Tokars, Jon Jacobs, J. Scott Daniels, Eric Dawson, Adrian Saldanha, Peter Chase, Yahira M. Baez-Santos, Craig W. Lindsley, Peter Hodder, Andrew D. Mesecar, Shaun R. Stauffer

Abstract

Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2–S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

Keywords

3CLpro, Severe acute respiratory syndrome, SARS, MERS, Coronavirus

The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines

Journal of Virological Methods
Volume 193, Issue 2, November 2013, Pages 639-646

Jose A. Regla-Nava, Jose M. Jimenez-Guardeño, Jose L. Nieto- Torres, Thomas M. Gallagher, Luis Enjuanes, Marta L. DeDiego

Abstract

Infection of conventional mice with a mouse adapted (MA15) severe acute respiratory syndrome (SARS) coronavirus (CoV) reproduces many aspects of human SARS such as pathological changes in lung, viremia, neutrophilia, and lethality. However, established mouse cell lines highly susceptible to mouse-adapted SARS-CoV infection are not available. In this work, efficiently transfectable mouse cell lines stably expressing the murine SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) have been generated. These cells yielded high SARS-CoV-MA15 titers and also served as excellent tools for plaque assays. In addition, in these cell lines, SARS-CoV-MA15 induced the expression of proinflammatory cytokines and IFN-β, mimicking what has been observed in experimental animal models infected with SARS-CoV and SARS patients. These cell lines are valuable tools to perform in vitro studies in a mouse cell system that reflects the species used for in vivo studies of SARS-CoV-MA15 pathogenesis.

Keywords

SARS, Coronavirus, Mouse adapted, Stably transformed murine cells, SARS-CoV receptor ACE2, Proinflammatory cytokines

Therapeutic Options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) – possible lessons from a systematic review of SARS-CoV therapy

International Journal of Infectious Diseases
Volume 17, Issue 10, October 2013, Pages e792-e798

Hisham Momattin, Khurram Mohammed, Alimuddin Zumla, Ziad A. Memish, Jaffar A. Al-Tawfiq

Abstract

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been detected in a number of countries in the Middle East and Europe with an apparently high mortality rate. It is phylogenetically related to the SARS coronavirus and has also been associated with severe respiratory illness as well as nosocomial transmission in healthcare settings. Current international recommendations do not support any specific therapies; however, there are a number of agents, which were used during the SARS epidemic of 2003. It is possible that these might be active against the related MERS coronavirus. We have reviewed the literature on the safety and efficacy of therapies used in patients with SARS with a view to their potential use in patients with MERS-CoV infections.

Keywords

MERS-CoV, Interferon, Ribavarin, SARS

Middle East respiratory syndrome coronavirus (MERS-CoV): challenges in identifying its source and controlling its spread

Microbes and Infection
Volume 15, Issues 8–9, July–August 2013, Pages 625-629

Lu Lu, Qi Liu, Lanying Du, Shibo Jiang

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV), a novel human coronavirus that caused outbreaks of a SARS-like illness in the Middle East, is now considered a threat to global public health. This review discusses the challenges in identifying the source of this fatal virus and developing effective and safe anti-MERS-CoV vaccines and therapeutics in order to control its spread and to combat any future pandemic.

Keywords

Coronavirus, MERS-CoV, SARS-CoV, Source, Vaccine, Therapeutics

Dieckol, a SARS-CoV 3CLpro inhibitor, isolated from the edible brown algae Ecklonia cava

Bioorganic & Medicinal Chemistry
Volume 21, Issue 13, 1 July 2013, Pages 3730-3737

Ji-Young Park, Jang Hoon Kim, Jung Min Kwon, Hyung- Jun Kwon, Hyung Jae Jeong, Young Min Kim, Doman Kim, Woo Song Lee, Young Bae Ryu

Abstract

SARS-CoV 3CLpro plays an important role in viral replication. In this study, we performed a biological evaluation on nine phlorotannins isolated from the edible brown algae Ecklonia cava. The nine isolated phlorotannins (1–9), except phloroglucinol (1), possessed SARS-CoV 3CLpro inhibitory activities in a dose-dependently and competitive manner. Of these phlorotannins (1–9), two eckol groups with a diphenyl ether linked dieckol (8) showed the most potent SARS-CoV 3CLpro trans/cis-cleavage inhibitory effects (IC50s = 2.7 and 68.1 μM, respectively). This is the first report of a (8) phlorotannin chemotype significantly blocking the cleavage of SARS-CoV 3CLpro in a cell-based assay with no toxicity. Furthermore, dieckol (8) exhibited a high association rate in the SPR sensorgram and formed extremely strong hydrogen bonds to the catalytic dyad (Cys145 and His41) of the SARS-CoV 3CLpro.

Keywords

Phlorotannin, SARS-CoV, Dieckol, Eckol, Ecklonia cava