scholarly journals Multi-Targeting of Functional Cysteines in Multiple Conserved SARS-CoV-2 Domains by Clinically Safe Zn-ejectors

2020 ◽  
Author(s):  
Karen Sargsyan ◽  
Chien-Chu Lin ◽  
Ting Chen ◽  
Cédric Grauffel ◽  
Yi-Ping Chen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Life Cycle ◽  
Broad Spectrum ◽  
Drug Targets ◽  
Viral Proteins ◽  
Term Treatment ◽  
Virus Life Cycle ◽  
Near Term ◽  
Physical Principles

<p>We present a near-term treatment strategy to tackle pandemic outbreaks of coronaviruses with no specific drugs/vaccines by combining evolutionary and physical principles to identify conserved viral domains containing druggable Zn-sites that can be targeted by clinically safe Zn-ejecting compounds. By applying this strategy to SARS-CoV-2 polyprotein-1ab, we predicted multiple labile Zn-sites in papain-like cysteine protease (PL<sup>pro</sup>), nsp10 transcription factor, and nsp13 helicase. These are attractive drug targets because they are highly conserved among coronaviruses and play vital structural/catalytic roles in viral proteins indispensable for viral replication. We show that five Zn-ejectors can release Zn<sup>2+ </sup>from PL<sup>pro</sup> and nsp10, and clinically-safe disulfiram and ebselen can covalently bind to the Zn-bound/catalytic cysteines in both proteins. Notably, disulfiram and ebselen inhibited PL<sup>pro</sup> protease activity with IC<sub>50</sub> in the μM range. We propose combining disulfiram/ebselen with broad-spectrum antivirals/drugs to target different conserved domains acting at various stages of the virus life cycle to synergistically inhibit SARS-CoV-2 replication and reduce the emergence of drug resistance.</p>

scholarly journals Multi-Targeting of Functional Cysteines in Multiple Conserved SARS-CoV-2 Domains by Clinically Safe Zn-ejectors

2020 ◽  
Author(s):  
Karen Sargsyan ◽  
Chien-Chu Lin ◽  
Ting Chen ◽  
Cédric Grauffel ◽  
Yi-Ping Chen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Life Cycle ◽  
Broad Spectrum ◽  
Drug Targets ◽  
Viral Proteins ◽  
Term Treatment ◽  
Virus Life Cycle ◽  
Near Term ◽  
Physical Principles

<div><div><div><p>We present a near-term treatment strategy to tackle pandemic outbreaks of coronaviruses with no specific drugs/vaccines by combining evolutionary and physical principles to identify conserved viral domains containing druggable Zn-sites that can be targeted by clinically safe Zn-ejecting compounds. By applying this strategy to SARS-CoV-2 polyprotein-1ab, we predicted multiple labile Zn-sites in papain-like cysteine protease (PLpro), nsp10 transcription factor, and nsp13 helicase. These are attractive drug targets because they are highly conserved among coronaviruses and play vital structural/catalytic roles in viral proteins indispensable for viral replication. We show that five Zn-ejectors can release Zn2+ from PLpro and nsp10, and clinically-safe disulfiram and ebselen can not only covalently bind to the Zn-bound/catalytic cysteines in both proteins, but also inhibit PLpro protease activity. We propose combining disulfiram/ebselen with broad-spectrum antivirals/drugs to target different conserved domains acting at various stages of the virus life cycle to synergistically inhibit SARS-CoV-2 replication and reduce the emergence of drug resistance.</p></div></div></div>

scholarly journals Multi-Targeting of Functional Cysteines in Multiple Conserved SARS-CoV-2 Domains by Clinically Safe Zn-ejectors

2020 ◽  
Author(s):  
Karen Sargsyan ◽  
Chien-Chu Lin ◽  
Ting Chen ◽  
Cédric Grauffel ◽  
Yi-Ping Chen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Life Cycle ◽  
Broad Spectrum ◽  
Drug Targets ◽  
Viral Proteins ◽  
Term Treatment ◽  
Virus Life Cycle ◽  
Near Term ◽  
Physical Principles

<div><div><div><p>We present a near-term treatment strategy to tackle pandemic outbreaks of coronaviruses with no specific drugs/vaccines by combining evolutionary and physical principles to identify conserved viral domains containing druggable Zn-sites that can be targeted by clinically safe Zn-ejecting compounds. By applying this strategy to SARS-CoV-2 polyprotein-1ab, we predicted multiple labile Zn-sites in papain-like cysteine protease (PLpro), nsp10 transcription factor, and nsp13 helicase. These are attractive drug targets because they are highly conserved among coronaviruses and play vital structural/catalytic roles in viral proteins indispensable for viral replication. We show that five Zn-ejectors can release Zn2+ from PLpro and nsp10, and clinically-safe disulfiram and ebselen can not only covalently bind to the Zn-bound/catalytic cysteines in both proteins, but also inhibit PLpro protease activity. We propose combining disulfiram/ebselen with broad-spectrum antivirals/drugs to target different conserved domains acting at various stages of the virus life cycle to synergistically inhibit SARS-CoV-2 replication and reduce the emergence of drug resistance.</p></div></div></div>

scholarly journals Reviewing Chandipura: A Vesiculovirus in Human Epidemics

2007 ◽  
Vol 27 (4-5) ◽  
pp. 275-298 ◽  
Author(s):  
Soumen Basak ◽  
Arindam Mondal ◽  
Smarajit Polley ◽  
Subhradip Mukhopadhyay ◽  
Dhrubajyoti Chattopadhyay
Keyword(s):  
Life Cycle ◽  
Vesicular Stomatitis Virus ◽  
Drug Targets ◽  
Viral Rna ◽  
Virus Life Cycle ◽  
Chandipura Virus ◽  
Comprehensive Picture ◽  
Vesicular Stomatitis ◽  
Potential Drug Targets ◽  
Shed Light

Chandipura virus, a member of the rhabdoviridae family and vesiculovirus genera, has recently emerged as human pathogen that is associated with a number of outbreaks in different parts of India. Although, the virus closely resembles with the prototype vesiculovirus, Vesicular Stomatitis Virus, it could be readily distinguished by its ability to infect humans. Studies on Chandipura virus while shed light into distinct stages of viral infection; it may also allow us to identify potential drug targets for antiviral therapy. In this review, we have summarized our current understanding of Chandipura virus life cycle at the molecular detail with particular interest in viral RNA metabolisms, namely transcription, replication and packaging of viral RNA into nucleocapsid structure. Contemporary research on otherwise extensively studied family member Vesicular Stomatitis Virus has also been addressed to present a more comprehensive picture of vesiculovirus life cycle. Finally, we reveal examples of protein economy in Chandipura virus life-cycle whereby each viral protein has evolved complexity to perform multiple tasks.

scholarly journals Ubiquitination Upregulates Influenza Virus Polymerase Function

2016 ◽  
Vol 90 (23) ◽  
pp. 10906-10914 ◽  
Author(s):  
James Kirui ◽  
Arindam Mondal ◽  
Andrew Mehle
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Viral Proteins ◽  
Polymerase Activity ◽  
Viral Gene ◽  
Viral Polymerase ◽  
Ubiquitin Proteasome Pathway ◽  
Virus Life Cycle ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACTThe influenza A virus polymerase plays an essential role in the virus life cycle, directing synthesis of viral mRNAs and genomes. It is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher-order ribonucleoprotein (RNP) complexes. The polymerase is regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including posttranslational modifications; however, the mechanisms are not fully understood. Here we demonstrate that ubiquitination plays an important role in stimulating polymerase activity. We show that all protein subunits in the RNP are ubiquitinated, but ubiquitination does not significantly alter protein levels. Instead, ubiquitination and an active proteasome enhance polymerase activity. Expression of ubiquitin upregulates polymerase function in a dose-dependent fashion, causing increased accumulation of viral RNA (vRNA), cRNA, and mRNA and enhanced viral gene expression during infection. Ubiquitin expression directly affects polymerase activity independent of nucleoprotein (NP) or ribonucleoprotein (RNP) assembly. Ubiquitination and the ubiquitin-proteasome pathway play key roles during multiple stages of influenza virus infection, and data presented here now demonstrate that these processes modulate viral polymerase activity independent of protein degradation.IMPORTANCEThe cellular ubiquitin-proteasome pathway impacts steps during the entire influenza virus life cycle. Ubiquitination suppresses replication by targeting viral proteins for degradation and stimulating innate antiviral signaling pathways. Ubiquitination also enhances replication by facilitating viral entry and virion disassembly. We identify here an addition proviral role of the ubiquitin-proteasome system, showing that all of the proteins in the viral replication machinery are subject to ubiquitination and this is crucial for optimal viral polymerase activity. Manipulation of the ubiquitin machinery for therapeutic benefit is therefore likely to disrupt the function of multiple viral proteins at stages throughout the course of infection.

scholarly journals Intracellular Hepatitis C Virus Modeling Predicts Infection Dynamics and Viral Protein Mechanisms

2018 ◽  
Vol 92 (11) ◽  
pp. e02098-17 ◽  
Author(s):  
Thomas R. Aunins ◽  
Katherine A. Marsh ◽  
Gitanjali Subramanya ◽  
Susan L. Uprichard ◽  
Alan S. Perelson ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Kinetic Data ◽  
Viral Proteins ◽  
Viral Life Cycle ◽  
Hcv Infection ◽  
Viral Rna ◽  
Model Parameters ◽  
Virus Life Cycle

ABSTRACTHepatitis C virus (HCV) infection is a global health problem, with nearly 2 million new infections occurring every year and up to 85% of these infections becoming chronic infections that pose serious long-term health risks. To effectively reduce the prevalence of HCV infection and associated diseases, it is important to understand the intracellular dynamics of the viral life cycle. Here, we present a detailed mathematical model that represents the full hepatitis C virus life cycle. It is the first full HCV model to be fit to acute intracellular infection data and the first to explore the functions of distinct viral proteins, probing multiple hypotheses ofcis- andtrans-acting mechanisms to provide insights for drug targeting. Model parameters were derived from the literature, experiments, and fitting to experimental intracellular viral RNA, extracellular viral titer, and HCV core and NS3 protein kinetic data from viral inoculation to steady state. Our model predicts higher rates for protein translation and polyprotein cleavage than previous replicon models and demonstrates that the processes of translation and synthesis of viral RNA have the most influence on the levels of the species we tracked in experiments. Overall, our experimental data and the resulting mathematical infection model reveal information about the regulation of core protein during infection, produce specific insights into the roles of the viral core, NS5A, and NS5B proteins, and demonstrate the sensitivities of viral proteins and RNA to distinct reactions within the life cycle.IMPORTANCEWe have designed a model for the full life cycle of hepatitis C virus. Past efforts have largely focused on modeling hepatitis C virus replicon systems, in which transfected subgenomic HCV RNA maintains autonomous replication in the absence of virion production or spread. We started with the general structure of these previous replicon models and expanded it to create a model that incorporates the full virus life cycle as well as additional intracellular mechanistic detail. We compared several different hypotheses that have been proposed for different parts of the life cycle and applied the corresponding model variations to infection data to determine which hypotheses are most consistent with the empirical kinetic data. Because the infection data we have collected for this study are a more physiologically relevant representation of a viral life cycle than data obtained from a replicon system, our model can make more accurate predictions about clinical hepatitis C virus infections.

scholarly journals Commentary on the Regulation of Viral Proteins in Autophagy Process

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Ching-Yuan Cheng ◽  
Pei-I Chi ◽  
Hung-Jen Liu
Keyword(s):  
Innate Immunity ◽  
Life Cycle ◽  
Current Knowledge ◽  
Viral Proteins ◽  
Host Cells ◽  
Cell Regulation ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Cellular Pathways ◽  
The Relationship

The ability to subvert intracellular antiviral defenses is necessary for virus to survive as its replication occurs only in the host cells. Viruses have to modulate cellular processes and antiviral mechanisms to their own advantage during the entire virus life cycle. Autophagy plays important roles in cell regulation. Its function is not only to catabolize aggregate proteins and damaged organelles for recycling but also to serve as innate immunity to remove intracellular pathogenic elements such as viruses. Nevertheless, some viruses have evolved to negatively regulate autophagy by inhibiting its formation. Even more, some viruses have employed autophagy to benefit their replication. To date, there are more and more growing evidences uncovering the functions of many viral proteins to regulate autophagy through different cellular pathways. In this review, we will discuss the relationship between viruses and autophagy and summarize the current knowledge on the functions of viral proteins contributing to affect autophagy process.

scholarly journals Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Elvira Cynthia Alves Horácio ◽  
Jéssica Hickson ◽  
Silvane Maria Fonseca Murta ◽  
Jeronimo Conceição Ruiz ◽  
Laila Alves Nahum
Keyword(s):  
Drug Resistance ◽  
Systems Biology ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Term Treatment ◽  
System Level ◽  
Treatment Protocols ◽  
Molecular Features ◽  
Antioxidant Defense Enzymes ◽  
Long Term Treatment

Neglected Tropical Diseases include a broad range of pathogens, hosts, and vectors, which represent evolving complex systems. Leishmaniasis, caused by different Leishmania species and transmitted to humans by sandflies, are among such diseases. Leishmania and other Trypanosomatidae display some peculiar features, which make them a complex system to study. Leishmaniasis chemotherapy is limited due to high toxicity of available drugs, long-term treatment protocols, and occurrence of drug resistant parasite strains. Systems biology studies the interactions and behavior of complex biological processes and may improve knowledge of Leishmania drug resistance. System-level studies to understand Leishmania biology have been challenging mainly because of its unusual molecular features. Networks integrating the biochemical and biological pathways involved in drug resistance have been reported in literature. Antioxidant defense enzymes have been identified as potential drug targets against leishmaniasis. These and other biomarkers might be studied from the perspective of systems biology and systems parasitology opening new frontiers for drug development and treatment of leishmaniasis and other diseases. Our main goals include: 1) Summarize current advances in Leishmania research focused on chemotherapy and drug resistance. 2) Share our viewpoint on the application of systems biology to Leishmania studies. 3) Provide insights and directions for future investigation.

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

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