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1.
STAR Protoc ; 3(3): 101468, 2022 09 16.
Article in English | MEDLINE | ID: covidwho-1895508

ABSTRACT

Nucleotide/nucleoside analogs (NAs) are important compounds used in antiviral drug development. To understand the action mode of NA drugs, we present an enzymology protocol to initially evaluate the intervention mechanism of the NTP forms of NAs on a coronaviral RNA-dependent RNA polymerase (RdRP). We describe the preparation of SARS-CoV-2 RdRP proteins and RNA constructs, followed by a primer-dependent RdRP assay to assess NTP forms of NAs. Two representative NA drugs, sofosbuvir and remdesivir, are used for demonstration of this protocol. For complete details on the use and execution of this protocol, please refer to Wu et al. (2021).


Subject(s)
Nucleosides , Nucleotides , RNA-Dependent RNA Polymerase , SARS-CoV-2 , Nucleosides/analogs & derivatives , Nucleosides/pharmacology , Nucleotides/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
2.
Drug Discov Today ; 27(7): 1945-1953, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1693694

ABSTRACT

With several US Food and Drug Administration (FDA)-approved drugs and high barriers to resistance, nucleoside and nucleotide analogs remain the cornerstone of antiviral therapies for not only herpesviruses, but also HIV and hepatitis viruses (B and C); however, with the exception of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which vaccines have been developed at unprecedented speed, there are no vaccines or small antivirals yet available for (re)emerging viruses, which are primarily RNA viruses. Thus, herein, we present an overview of ribonucleoside analogs recently developed and acting as inhibitors of the viral RNA-dependent RNA polymerase (RdRp). They are new lead structures that will be exploited for the discovery of new antiviral nucleosides.


Subject(s)
Antiviral Agents , Nucleosides , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Humans , Nucleosides/analogs & derivatives , Nucleosides/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , United States
3.
Nature ; 604(7904): 134-140, 2022 04.
Article in English | MEDLINE | ID: covidwho-1671590

ABSTRACT

The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half1 ( https://www.who.org/ ). Individuals with SARS-CoV-2 infection typically develop mild-to-severe flu-like symptoms, whereas infection of a subset of individuals leads to severe-to-fatal clinical outcomes2. Although vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics, which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs. Here we screened approximately 18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validated 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Among these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2, suggesting a clinical path forward.


Subject(s)
Antiviral Agents , Drug Evaluation, Preclinical , Nucleosides , Pyrimidines , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cell Line , Cytidine/analogs & derivatives , Humans , Hydroxylamines , Nucleosides/analogs & derivatives , Nucleosides/pharmacology , Pyrimidines/pharmacology , SARS-CoV-2/drug effects
4.
Antiviral Res ; 195: 105180, 2021 11.
Article in English | MEDLINE | ID: covidwho-1415189

ABSTRACT

Galidesivir (BCX4430) is an adenosine nucleoside analog that is broadly active in cell culture against several RNA viruses of various families. This activity has also been shown in animal models of viral disease associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever viruses. In many cases, the compound is more efficacious in animal models than cell culture activity would predict. Based on favorable data from in vivo animal studies, galidesivir has recently undergone evaluation in several phase I clinical trials, including against severe acute respiratory syndrome coronavirus 2, and as a medical countermeasure for the treatment of Marburg virus disease.


Subject(s)
Adenine/analogs & derivatives , Adenosine/analogs & derivatives , Antiviral Agents/pharmacology , Pyrrolidines/pharmacology , Adenine/pharmacology , Adenosine/pharmacology , Animals , Clinical Trials, Phase I as Topic , Drug Evaluation, Preclinical , Marburgvirus/drug effects , Nucleosides/analogs & derivatives , SARS-CoV-2/drug effects
5.
Molecules ; 26(11)2021 Jun 07.
Article in English | MEDLINE | ID: covidwho-1259549

ABSTRACT

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.


Subject(s)
Antiviral Agents/chemical synthesis , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Nucleosides/analogs & derivatives , Nucleosides/chemical synthesis , SARS-CoV-2/enzymology , Chemistry, Pharmaceutical/methods , In Vitro Techniques , SARS-CoV-2/drug effects
6.
Viruses ; 13(4)2021 04 13.
Article in English | MEDLINE | ID: covidwho-1187060

ABSTRACT

The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.


Subject(s)
Antiviral Agents/pharmacology , Nucleosides/analogs & derivatives , Nucleosides/pharmacology , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides , Animals , Antiviral Agents/chemistry , COVID-19/drug therapy , Hemorrhagic Fever, Ebola/drug therapy , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Mutagenesis , Pyrazines , Ribavirin , SARS-CoV-2 , Virus Replication/drug effects , Zika Virus/drug effects , Zika Virus Infection/drug therapy
7.
Eur J Clin Pharmacol ; 77(9): 1297-1307, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1116615

ABSTRACT

AIMS: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications. SUBJECT AND METHOD: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, "SARS-CoV-2," "COVID-19," "antivirals," "therapy"), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19. RESULTS: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir. DISCUSSION: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Clinical Trials as Topic , Drug Combinations , Drug Interactions , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Humans , Nucleosides/analogs & derivatives , Nucleotides/pharmacology , Nucleotides/therapeutic use , Oxygen/blood , SARS-CoV-2
8.
J Chem Inf Model ; 61(3): 1402-1411, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1114679

ABSTRACT

SARS-CoV-2 is a positive-sense RNA virus that requires an RNA-dependent RNA polymerase (RdRp) for replication of its viral genome. Nucleoside analogs such as Remdesivir and ß-d-N4-hydroxycytidine are antiviral candidates and may function as chain terminators or induce viral mutations, thus impairing RdRp function. Recently disclosed Cryo-EM structures of apo, RNA-bound, and inhibitor-bound SARS-CoV-2 RdRp provided insight into the inhibitor-bound structure by capturing the enzyme with its reaction product: Remdesivir covalently bound to the RNA primer strand. To gain a structural understanding of the binding of this and several other nucleoside analogs in the precatalytic state, molecular models were developed that predict the noncovalent interactions to a complex of SARS-CoV-2 RdRp, RNA, and catalytic metal cations. MM-GBSA evaluation of these interactions is consistent with resistance-conferring mutations and existing structure-activity relationship (SAR) data. Therefore, this approach may yield insights into antiviral mechanisms and guide the development of experimental drugs for COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , Nucleosides/analogs & derivatives , Nucleosides/pharmacology , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/metabolism , Drug Design , Drug Discovery , Humans , Molecular Docking Simulation , SARS-CoV-2/metabolism
9.
Int J Mol Sci ; 21(24)2020 Dec 21.
Article in English | MEDLINE | ID: covidwho-1006952

ABSTRACT

Since the outbreak of coronavirus disease 2019 (COVID-19) was first identified, the world has vehemently worked to develop treatments and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented speed. Few of the repositioned drugs for COVID-19 have shown that they were efficacious and safe. In contrast, a couple of vaccines against SARS-CoV-2 will be ready for mass rollout early next year. Despite successful vaccine development for COVID-19, the world will face a whole new set of challenges including scale-up manufacturing, cold-chain logistics, long-term safety, and low vaccine acceptance. We highlighted the importance of knowledge sharing and collaboration to find innovative answers to these challenges and to prepare for newly emerging viruses.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/drug therapy , COVID-19/prevention & control , Drug Repositioning , Antimalarials/therapeutic use , Chloroquine/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Nucleosides/analogs & derivatives , Nucleosides/therapeutic use , Pandemics/prevention & control , Protease Inhibitors/therapeutic use , Public Health , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
10.
Molecules ; 25(7)2020 Mar 27.
Article in English | MEDLINE | ID: covidwho-831217

ABSTRACT

For decades, nucleosides and nucleotides have formed the cornerstone of antiviral, antiparasitic and anticancer therapeutics and have been used as tools in exploring nucleic acid structure and function [...].


Subject(s)
Nucleic Acids/chemistry , Nucleosides/chemistry , Nucleotides/chemistry , Anti-Bacterial Agents/pharmacology , Antiprotozoal Agents/pharmacology , Antiviral Agents/pharmacology , Computational Biology , Humans , Nucleosides/analogs & derivatives , Nucleosides/metabolism , Nucleosides/pharmacology , Nucleotides/metabolism
11.
Mini Rev Med Chem ; 20(18): 1900-1907, 2020.
Article in English | MEDLINE | ID: covidwho-706996

ABSTRACT

The global spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes COVID-19 has become a source of grave medical and socioeconomic concern to human society. Since its first appearance in the Wuhan region of China in December 2019, the most effective measures of managing the spread of SARS-CoV-2 infection have been social distancing and lockdown of human activity; the level of which has not been seen in our generations. Effective control of the viral infection and COVID-19 will ultimately depend on the development of either a vaccine or therapeutic agents. This article highlights the progresses made so far in these strategies by assessing key targets associated with the viral replication cycle. The key viral proteins and enzymes that could be targeted by new and repurposed drugs are discussed.


Subject(s)
COVID-19/therapy , Coronavirus 3C Proteases/antagonists & inhibitors , RNA Helicases/antagonists & inhibitors , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Antibodies/therapeutic use , Antiprotozoal Agents/therapeutic use , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Humans , Nucleosides/analogs & derivatives , Nucleosides/metabolism , Nucleosides/therapeutic use , Protease Inhibitors/therapeutic use , RNA Helicases/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology
12.
Life Sci ; 253: 117592, 2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-14903

ABSTRACT

AIMS: A new human coronavirus (HCoV), which has been designated SARS-CoV-2, began spreading in December 2019 in Wuhan City, China causing pneumonia called COVID-19. The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier. There is concern that this new virus will spread around the world as did the previous two HCoVs-Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)-each of which caused approximately 800 deaths in the years 2002 and 2012, respectively. Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries. MAIN METHODS: In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses. KEY FINDINGS: The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp. In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically. SIGNIFICANCE: The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19. The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Molecular Docking Simulation , Nucleic Acid Synthesis Inhibitors/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Humans , Nucleic Acid Synthesis Inhibitors/pharmacology , Nucleosides/analogs & derivatives , SARS-CoV-2
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