A comprehensive procedure for antiviral inhibitor discovery using EV71 as an example

Cao, Lin; Zhu, Shijun; Wang, Yaxin; Lou, Zhiyong; Sun, Yuna

doi:10.1007/s41048-015-0006-z

Cited by 5 publications

(3 citation statements)

References 6 publications

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“…We developed a highly efficient assay (12,13) and discovered a series of potent anti-EV71 PIs targeting EV71 3C pro (14)(15)(16)(17)(18). Among them, NK-1.8k (a peptidyl aldehyde derivative) and compound 9 and NK-1.9k (cyanohydrin derivatives) have the highest potencies against EV71 infection with good pharmacological properties, but they still exhibit distinct features.…”

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confidence: 99%

Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

Wang

Cao

Zhai

et al. 2017

Antimicrob Agents Chemother

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Hand-foot-and-mouth disease (HFMD), caused by enterovirus, is a threat to public health worldwide. To date, enterovirus 71 (EV71) has been one of the major causative agents of HFMD in the Pacific-Asia region, and outbreaks with EV71 cause millions of infections. However, no drug is currently available for clinical therapeutics. In our previous works, we developed a set of protease inhibitors (PIs) targeting the EV71 3C protease (3C pro ). Among these are NK-1.8k and NK-1.9k, which have various active groups and high potencies and selectivities. In the study described here, we determined the structures of the PI NK-1.8k in complex with wild-type (WT) and drug-resistant EV71 3C pro . Comparison of these structures with the structure of unliganded EV71 3C pro and its complex with AG7088 indicated that the mutation of N69 to a serine residue destabilized the S2 pocket. Thus, the mutation influenced the cleavage activity of EV71 3C pro and the inhibitory activity of NK-1.8k in an in vitro protease assay and highlighted that site 69 is an additional key site for PI design. More information for the optimization of the P1= to P4 groups of PIs was also obtained from these structures. Together with the results of our previous works, these in-depth results elucidate the inhibitory mechanism of PIs and shed light to develop PIs for the clinical treatment of infections caused by EV71 and other enteroviruses.KEYWORDS EV71, protease, inhibitor, crystal structure, mechanism H and-foot-and-mouth disease (HFMD) is a common viral illness among infants and young children that causes fever, sore throat, blisters, pharyngitis, mouth ulcers, and a rash on the hands and feet (1, 2). Enterovirus 71 (EV71) has been the main causative agent of HFMD in recent years. Unfortunately, no drugs for the treatment of this disease are available. EV71 is classified as a member of Enterovirus species A within the genus Enterovirus of the Picornaviridae family (3). In the virus replication cycle, the 7.4-kb positive-sense, single-stranded RNA genome of EV71 is translated into a polyprotein which is subdivided into three primary precursors, P1, P2, and P3. Four structural proteins, VP1 to VP4, derived from the P1 portion, form the capsid of the mature virion (4), and the P2 and P3 regions are cleaved by viral proteases, forming seven individual nonstructural proteins, 2A, 2B, 2C, 3A, 3B, 3C, and 3D (5, 6). The correct replication of EV71 is dependent on the effective cleavage of the viral polyprotein by viral 2A protease (2A pro ) and 3C protease (3C pro ) (7). Of these two proteases, 3C pro not only takes major responsibility for polyprotein cleavage, with the exception that 2A pro is responsible for the cleavage of VP1/2A and 3C/3D, but also plays multiple roles in various biological processes (8).EV71 3C pro is a classical cysteine protease. Cysteine proteases are a large family containing many members functioning in various physiological processes (9). The

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confidence: 99%

Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

Wang

Cao

Zhai

et al. 2017

Antimicrob Agents Chemother

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“…Virus titration. For EV71-GFP virus, virus titers were determined by measuring the expression level of GFP in RD cells (15,37). The measurement was performed by seeding 3 ϫ 10 4 RD cells per well in 96-well microtiter plates.…”

Section: Methodsmentioning

confidence: 99%

A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus

Guo

Wang

Cao

et al. 2016

Antimicrob Agents Chemother

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f Enterovirus 71 (EV71) (Picornaviridae family) and hepatitis C virus (HCV) (Flaviviridae family) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1-acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1-acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2A pro ) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2A pro is the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2A pro , confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti-EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections. E nterovirus 71 (EV71) is one of the major etiological agents of human hand, foot, and mouth disease (HFMD) in the AsiaPacific region. Particularly, young children and immunodeficient populations are more susceptible to EV71 infection. EV71 infection results in severe aseptic meningitis, encephalitis, myocarditis, acute flaccid paralysis, and pulmonary edema, which lead to high fatality rates (1, 2). Chronic infection with hepatitis C virus (HCV) affects 180 million people worldwide, and 350,000 people die each year due to HCV-related complications (3). Hepatitis C not only affects the liver function but also induces liver fibrosis and cirrhosis, eventually leading to liver cancer (4).Both EV71 and HCV are positive-sense single-stranded RNA (ϩssRNA) viruses. EV71 is a member of the Enterovirus genus within the Picornaviridae family (5-7). The genome of EV71 encodes a polyprotein that is cleaved through viral proteases to generate four structural proteins (VP1 to VP4) required for viral capsid formation and seven nonstructural proteins (2A pro , 2B, 2C, 3A, 3B, 3C pro , and 3D pol ) for viral replication (8-10). HCV is a member of the Hepacivirus genus in the Flaviviridae family. The translated polyprotein of HCV is further processed into the structural proteins, including core protein and envelope glycoproteins E1 and E2; the nonstructural proteins are processed into NS2, NS3, NS4A, NS4B, NS5A, and NS5B (11).The successful replication of most viruses depends on the correct proteolytic processing of polyproteins. EV71 employs two viral proteases: 2A ...

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“…The rate of discovery and development of antiviral agents has declined significantly in recent decades, and pathogenic viruses have become serious and have been continuously developing resistance to marketed antiviral agents, imposing a frightening medical problem worldwide [1,2]. Furthermore, antiviral agents face serious challenges owing to a reduction in the number of newly approved drugs and a lack of knowledge about the pathways and mechanisms of these diseases [3,4].…”

Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Approved Anti-Inflammatory Drugs and Prospects for Drug Repurposing: A review

Abdallah,

Abdulaziz,

Elhadi

et al. 2023

JAMPS

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Drug discovery and development are lengthy and expensive processes that face serious challenges. A new compound must not only produce the desired response with minimal side effects but must also demonstrate better activity than existing drugs. Thus, modification of existing drugs is easier than discovery of new drugs. Furthermore, the rate of development of new antiviral agents has declined significantly in recent decades, and pathogenic viruses have become more serious and have developed resistance against antiviral drugs. Hence, owing to multidrug resistance, severe side effects, and the emergence of new virus types, there is an urgent need for the development of new alternative or synergistic antiviral drugs with minimal side effects. Anti-inflammatory drugs represent a group of drugs with broad clinical applications and remain one of the most widely used medications worldwide. They can relieve the most common symptoms of viral infections (pain and fever). Thus, many researchers have screened for antiviral activities among the marketed anti-inflammatory drugs against different types of viral infections, based on the observed antiviral activity in different preclinical and clinical studies. This mini-review article summarizes preclinical studies (in silico, in vitro, and in vivo) that evaluated the antiviral activity of approved anti-inflammatory drugs.

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A comprehensive procedure for antiviral inhibitor discovery using EV71 as an example

Cited by 5 publications

References 6 publications

Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus

Antiviral Activity of Approved Anti-Inflammatory Drugs and Prospects for Drug Repurposing: A review

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