Author: Yang, Qingyu ; Huang, Rui ; Zhu, Guangyan ; Zhang, Dingyu ; Lin, Binbin ; Peng, Ke ; Wang, Qiongya ; Huang, Chaolin ; Wu, Chengyuan ; Ren, Fuli ; Wu, Ying ; Hu, Xujuan ; Zhao, Dingran

Enterovirus 71 (EV71), a small, single-stranded, positive-sense RNA virus belonging to the enterovirus genus in the family Picornaviridae, causes hand, foot, and mouth disease. Although EV71 seriously threatens to public health, no effective antiviral drugs are available for treating this disease. In this study, we found that ML390, a dihydroorotate dehydrogenase inhibitor, has potential anti-EV71 activity. ML390 dose-dependently inhibited EV71 replication with IC₅₀ and selectivity index values of 0.06601 μM and 156.5, respectively. Supplementation with the downstream product orotate significantly suppressed the ability of ML390 to inhibit EV71 replication. Moreover, an adequate supply of exogenous uridine and cytosine suppressed the anti-EV71 activity of ML390. Thus, the antiviral activity of ML390 is mediated by the inhibition of the pyrimidine synthesis pathway. In an EV71-infected mouse model, ML390 reduced the load of EV71 in the brain, liver, heart, spleen, front legs, and hind legs, and significantly increased the survival rate of the mice infected by EV71. ML390 shows potential for the treatment of hand, foot, and mouth disease caused by EV71 infection.

01 Oct 2022·Journal of Medical Virology

Identification of clinical candidates against West Nile virus by activity screening in vitro and effect evaluation in vivo

Article

Author: Tang, Hailin ; Ren, Ruiwen ; Liu, Yan ; Qi, Zhongtian ; He, Yanhua ; Zhao, Ping ; Liu, Yang ; Peng, Haoran

AbstractThe West Nile virus (WNV) is a member of the flavivirus and is known to cause encephalitis. There is currently no specific treatment for WNV infection. Repurposing of clinically approved drugs appeared promising for rapidly identifying effective, safe, and readily available candidates for antiviral drugs. Here, we screened the small‐molecule compounds with anti‐WNV activity from 978 Food Drug Administration‐approved drugs. Four compounds, including cilnidipine, mycophenolate mofetil, nitazoxanide, and teriflunomide, were found to efficiently abrogate WNV infection in Vero cells and human neuroblastoma SH‐SY5Y cells. The four compounds also exert broad‐spectrum antiviral activity against the Zika virus, Japanese encephalitis virus, yellow fever virus, tick‐borne encephalitis virus, and chikungunya virus. Furthermore, nitazoxanide (a synthetic benzamide) and teriflunomide (an inhibitor of dihydroorotate dehydrogenase, DHODH) protected 20% and 40% of mice from lethal WNV challenge, respectively. Both drugs, which are orally bioavailable and have been approved clinically for many years, may be promising therapeutics for WNV infection. Moreover, the other two DHODH inhibitors, ML390 and vidofludimus, also displayed potent activity against WNV infection in vitro and in vivo.

08 Dec 2016·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia

Q3 · MEDICINE

Article

Author: Lewis, Timothy A. ; Rustiguel, Joane K. ; Muñoz, Benito ; Sykes, David B. ; Schreiber, Stuart L. ; Nonato, Maria Cristina ; Scadden, David T. ; Law, Jason M.

Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.

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Indication	Highest Phase	Country/Location	Organization	Date
Adult Acute Myeloblastic Leukemia	Preclinical	US	Harvard University	22 Sep 2016
Adult Acute Myeloblastic Leukemia	Preclinical	CN	Shanghai Schering Plough Pharmaceutical Co. Ltd.	22 Sep 2016
Adult Acute Myeloblastic Leukemia	Preclinical	US	The General Hospital Corp.	22 Sep 2016

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