scholarly journals Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease

2021 ◽  
Vol 22 (22) ◽  
pp. 12134
Author(s):  
Yuxi Lin ◽  
Ruochen Zang ◽  
Yanlong Ma ◽  
Zhuoya Wang ◽  
Li Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Small Molecule ◽  
Drug Target ◽  
Antiviral Drug ◽  
High Morbidity ◽  
Lead Compound ◽  
Human Beings ◽  
Main Protease ◽  
Ic50 Value

Coronaviruses cause diseases in humans and livestock. The SARS-CoV-2 is infecting millions of human beings, with high morbidity and mortality worldwide. The main protease (Mpro) of coronavirus plays a pivotal role in viral replication and transcription, which, in theory, is an attractive drug target for antiviral drug development. It has been extensively discussed whether Xanthohumol is able to help COVID-19 patients. Here, we report that Xanthohumol, a small molecule in clinical trials from hops (Humulus lupulus), was a potent pan-inhibitor for various coronaviruses by targeting Mpro, for example, betacoronavirus SARS-CoV-2 (IC50 value of 1.53 μM), and alphacoronavirus PEDV (IC50 value of 7.51 μM). Xanthohumol inhibited Mpro activities in the enzymatical assays, while pretreatment with Xanthohumol restricted the SARS-CoV-2 and PEDV replication in Vero-E6 cells. Therefore, Xanthohumol is a potent pan-inhibitor of coronaviruses and an excellent lead compound for further drug development.

scholarly journals Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Science ◽  
2020 ◽  
Vol 368 (6489) ◽  
pp. 409-412 ◽  
Author(s):  
Linlin Zhang ◽  
Daizong Lin ◽  
Xinyuanyuan Sun ◽  
Ute Curth ◽  
Christian Drosten ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Severe Acute Respiratory Syndrome ◽  
Drug Target ◽  
Essential Role ◽  
Potent Inhibitor ◽  
Amide Bond ◽  
Lead Compound ◽  
X Ray ◽  
Main Protease

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

scholarly journals Progress in Anti-Mammarenavirus Drug Development

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1187
Author(s):  
Yu-Jin Kim ◽  
Victor Venturini ◽  
Juan C. de la Torre
Keyword(s):  
Drug Development ◽  
Current Knowledge ◽  
Antiviral Drug ◽  
High Morbidity ◽  
Off Label Use ◽  
Vaccine Candidates ◽  
Off Label ◽  
The Past ◽  
Human Infections ◽  
Significant Mortality

Mammarenaviruses are prevalent pathogens distributed worldwide, and several strains cause severe cases of human infections with high morbidity and significant mortality. Currently, there is no FDA-approved antiviral drugs and vaccines against mammarenavirus and the potential treatment option is limited to an off-label use of ribavirin that shows only partial protective effect and associates with side effects. For the past few decades, extensive research has reported potential anti-mammarenaviral drugs and their mechanisms of action in host as well as vaccine candidates. This review describes current knowledge about mammarenavirus virology, progress of antiviral drug development, and technical strategies of drug screening.

scholarly journals Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 106
Author(s):  
Camilla Isgrò ◽  
Anna Maria Sardanelli ◽  
Luigi Leonardo Palese
Keyword(s):  
Therapeutic Strategy ◽  
Ethacrynic Acid ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
High Morbidity ◽  
Global Pandemic ◽  
Main Protease ◽  
Starting Point ◽  
Effective Therapeutic Strategy

In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.

scholarly journals New Drugs - From Necessity to Delivery

2018 ◽  
Vol 31 (2) ◽  
pp. 69-75
Author(s):  
Ewa Kedzierska ◽  
Lila Dabkowska ◽  
Tomasz Krzanowski ◽  
Ewa Gibula ◽  
Jolanta Orzelska-Gorka ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Design ◽  
Drug Development ◽  
New Drugs ◽  
Google Scholar ◽  
Lead Compound ◽  
New Drug ◽  
Preclinical Trials ◽  
The Way

Abstract How to get a new drug to market? How much time does it take to go from the idea to implementation? In this study we followed the path drugs take from synthesis to introduction to the market. In doing so, articles in the PubMed and the Google Scholar database have been analyzed using the keywords: drug development, drug design, lead compound, preclinical trials, clinical trials. The available literature was subjectively selected due to its usefulness in the topic. Based on the obtained articles, we presented the stages that a would-be drug takes on the way from the idea to marketing. Herein, it is underlined that the process of creating new drugs is long, extremely labor-intensive, and involves many restrictions in the context of the use of animals, as well as humans

scholarly journals N-Terminal finger stabilizes the reversible feline drug GC376 in SARS-CoV-2 Mpro

2021 ◽  
Author(s):  
Elena Arutyunova ◽  
Muhammad Bashir Khan ◽  
Conrad Fischer ◽  
Jimmy Lu ◽  
Tess Lamer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Chemical Properties ◽  
Virus Growth ◽  
Live Virus ◽  
Mechanism Of Inhibition ◽  
Main Protease ◽  
The Stability ◽  
Insight Into ◽  
Broad Specificity

AbstractThe main protease (Mpro, also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug’s properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar Ki values with the Mpro from both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 Mpro. The comparison of a new X-ray crystal structure of Mpro from SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 Mpro, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the Mpro, which facilitates coordination of the drug’s P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.

scholarly journals Model Based Evaluation of Hypersensitivity Adverse Drug Reactions to Antimicrobial Agents in Children

2021 ◽  
Vol 12 ◽  
Author(s):  
Abdelbaset A. Elzagallaai ◽  
Michael J. Rieder
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Adverse Drug Reactions ◽  
Current Knowledge ◽  
Drug Hypersensitivity ◽  
High Morbidity ◽  
Hypersensitivity Reactions ◽  
Drug Reactions ◽  
Model Based ◽  
Drug Hypersensitivity Reactions

Drug use in children is–in most cases–supported by extrapolation of data generated from clinical trials in adult populations. This puts children at higher risk of developing adverse drug reactions (ADRs) due to “off-label” use of drugs and dosing issues. Major types of ADRs are drug hypersensitivity reactions, an idiosyncratic type of ADRs that are largely unpredictable and can cause high morbidity and mortality in a hard-to-identify specific population of patients. Lack of a complete understanding of the pathophysiology of DHRs and their unpredictive nature make them problematic in clinical practice and in drug development. In addition, ethical and legal obstacles hinder conducting large clinical trials in children, which in turn make children a “therapeutic orphan” where clear clinical guidelines are lacking, and practice is based largely on the personal experience of the clinician, hence making modeling desirable. This brief review summarizes the current knowledge of model-based evaluation of diagnosis and management of drug hypersensitivity reactions (DHRs) to antimicrobial drugs in the pediatric population. Ethical and legal aspects of drug research in children and the effect of different stages of child development and other factors on the risk of DHRs are discussed. The role of animal models, in vitro models and oral provocation test in management of DHRs are examined in the context of the current understanding of the pathophysiology of DHRs. Finally, recent changes in drug development legislations have been put forward to encourage drug developers to conduct trials in children clearly indicate the urgent need for evidence to support drug safety in children and for modeling to guide these clinical trials.

scholarly journals A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease

2020 ◽  
Author(s):  
Jeremy D. Baker ◽  
Rikki L. Uhrich ◽  
Gerald C. Kraemer ◽  
Jason E. Love ◽  
Brian C. Kraemer
Keyword(s):  
Hepatitis C ◽  
Drug Development ◽  
Large Scale ◽  
Previous History ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Drug Repurposing ◽  
Main Protease ◽  
Approved Drugs

AbstractThe SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic 1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly. The overall case fatality rate for COVID-19 is estimated to be ∼2.3% overall 3 and 32.3% in hospitalized patients age 70-79 years 4. Therapeutic options for treating the underlying viremia in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ∼6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found ∼50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 μM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including Boceprevir (IC50=0.95 μM), Ciluprevir (20.77μM). Narlaprevir (IC50=1.10μM), and Telaprevir (15.25μM). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.

scholarly journals POTENTIAL PHYTOCONSTITUENTS FROM NATURAL PRODUCTS FOR COMBATING AGAINST CORONAVIRUS DISEASE-19 (SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS‐2) - A REVIEW

2021 ◽  
pp. 8-18
Author(s):  
CHANDRASEKAR R ◽  
SIVAGAMI B ◽  
SATHEESH KUMAR G
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Medicinal Plants ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Infection ◽  
Viral Infections ◽  
Critical Role ◽  
Antiviral Drug ◽  
World Health ◽  
Human Beings

Coronavirus called as coronavirus diseases (COVID)-19 (severe acute respiratory syndrome coronavirus [SARS‐CoV]‐2) is a viral infection which is spreading to a great extent and affecting many people worldwide, many developed and developing countries are severely affected by the virus. The World Health Organization (WHO) is taking serious preventive measures to stop this viral infection worldwide. The coronavirus is a big threat to human beings and controlling the emerging viral infections is a global concern. Antiviral drug such as Remdesivir has been approved by the FDA, but combating against these viral infections is a great challenge to scientists and researchers with the available few antiviral drugs due to severe side effects and toxicity. Many drugs such as hydroxy chloroquin, Remdesivir, and vaccines have been recommended for combating this virus. Few Polyherbal formulations and Ayurvedic formulations containing antiviral phytoconstituents have been recommended to boost the immunity. Some drugs and phytoconstituents are under different phases of human clinical trials. The currently available synthetic drugs and vaccines for the treatment of viral infections have severe side effects. Medicinal plants play a critical role in treating viral infections by developing immunity against viral diseases. Some medicinal plants which were used as antipyretic, analgesic, and anti-inflammatory activity helped in treating various diseases and viral infections. Many plants contain flavonoids such as quercetin, luteolin, apigenin, and polyphenols such as thymoquinone, phytosteroids such as cucurbitacin and others which may likely to act as antioxidants and immunomodulatory that can fight against COVID-19. The current review provides information on phytochemical constituents present in medicinal plants, their mechanism of action, in silico molecular docking studies and human clinical trials to treat viral disorders.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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