Targeting Chikungunya Virus Entry: alternatives for new inhibitors in drug discovery

2021 ◽  
Vol 28 ◽  
Author(s):  
Leandro Rocha Silva ◽  
Érica Erlanny da Silva Rodrigues ◽  
Jamile Taniele-Silva ◽  
Letícia Anderson ◽  
João Xavier de Araújo-Júnior ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Viral Entry ◽  
Chikungunya Virus ◽  
Viral Disease ◽  
Virus Budding ◽  
Drug Candidates ◽  
Entry Inhibitors ◽  
Repurposed Drugs ◽  
Approved Drugs ◽  
Key Steps

: Chikungunya virus (CHIKV) is an Alphavirus (Togaviridae) responsible for Chikungunya fever (CHIKF) that is mainly characterized by a severe polyarthralgia, in which it is transmitted by the bite of infected Aedes aegypti and Ae. albopictus mosquitoes. Nowadays, there no licensed vaccines or approved drugs to specifically treat this viral disease. Structural viral proteins participate in key steps of its replication cycle, such as viral entry, membrane fusion, nucleocapsid assembly, and virus budding. In this context, envelope E3-E2-E1 glycoproteins complex could be targeted for designing new drug candidates. In this review, aspects of the CHIKV entry process are discussed to provide insights to assist the drug discovery process. Moreover, several natural, nature-based and synthetic compounds, as well as repurposed drugs and virtual screening, are also explored as alternatives for developing CHIKV entry inhibitors. Finally, we provided a complimentary analysis of studies involving inhibitors that were not explored by in silico methods. Based on this, Phe118, Val179, and Lys181 were found to be the most frequent residues, being present in 89.6, 82.7, and 93.1% of complexes, respectively. Lastly, some chemical aspects associated with interactions of these inhibitors and mature envelope E3-E2-E1 glycoproteins’ complex were discussed to provide data for scientists worldwide, supporting their search for new inhibitors against this emerging arbovirus.

Drug Discovery by Drug Repurposing: Combating COVID-19 in the 21st Century

2020 ◽  
Vol 20 ◽  
Author(s):  
Nitesh Sanghai ◽  
Kashfia Shafiq ◽  
Geoffrey K. Tranmer
Keyword(s):  
Drug Discovery ◽  
Drug Repurposing ◽  
Compassionate Use ◽  
Drug Candidates ◽  
Working Day ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Day By Day ◽  
Potential Use

: Due to the rapidly developing nature of the current COVID-19 outbreak and its almost immediate humanitarian and economic toll, coronavirus drug discovery efforts have largely focused on generating potential COVID-19 drug candidates as quickly as possible. Globally, scientists are working day and night to find the best possible solution to treat the deadly virus. During the first few months of 2020, the SARS-CoV-2 outbreak quickly developed into a pandemic, with a mortality rate that was increasing at an exponential rate day by day. As a result, scientists have turned to a drug repurposing approach, to rediscover the potential use and benefits of existing approved drugs. Currently, there is no single drug approved by the U.S. Food and Drug Administration (FDA), for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) that causes COVID-19. Based on only in-vitro studies, several active drugs are already in the clinical pipeline, made possible by following the compassionate use of medicine protocols. This method of repurposing and the use of existing molecules like Remdesivir (GS-5734), Chloroquine, Hydroxychloroquine, etc. has proven to be a landmark in the field of drug rediscovery. In this review article we will discuss the repurposing of medicines for treating the deadly novel coronavirus (SARS-CoV-2).

scholarly journals Repurposing of FDA approved drugs targeting Main protease MPro for SARS-CoV-2

2020 ◽  
Author(s):  
Suryakant Tiwari ◽  
Raghav Jain ◽  
Indrani Banerjee
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Active Site ◽  
Ligand Docking ◽  
Kcal Mole ◽  
Main Protease ◽  
Alternative Approach ◽  
Repurposed Drugs ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV-2 is one of the greatest pandemics in the history. There is no medicine or vaccine yet discovered to control the outbreak. The paper deals with repurposing existing drugs to control the outbreak of SARS-CoV-2 virus.Ten FDA-approved drugs namely Indinavir, Nelfinavir, Letermovir, Irinotecan, Elbasvir, Saquinavir, Darunavir, Raltegravir, Atazanavir and Amprenavir were studied. In silico methods for virtual screening of protein-ligand docking of these drugs against SARS-CoV-2 MPro was performed. The binding efficiency of the drugs against viral main protease MPro was significantly high to inhibit SARS-CoV-2.The results confirmed that Atazanavir, Nelfinavir, and Letermovir not only occupied the active site of Mpro but also showed increased binding affinity (-10.36 kcal/mole, -9.47 kcal/mole and -9.43 kcal/mole) even more than of control drugs of Lopinavir (-8.71 kcal/mole) and Ritonavir (-8.08 kcal/mole). These repurposed drugs can be used in combination or individually as an alternative approach for rapid drug discovery against SARS-CoV-2

scholarly journals Current Drug Repurposing Strategies in Treatment of COVID-19

2020 ◽  
Vol 13 (3) ◽  
pp. 125-131
Author(s):  
Kapish Kapoor ◽  
Abbas Sanawedwala ◽  
Deeksha Rajput ◽  
Shreyansh Bhardwaj ◽  
Kriti Shrivastav ◽  
...  
Keyword(s):  
Drug Discovery ◽  
General Population ◽  
Drug Repurposing ◽  
Viral Disease ◽  
Current Drug ◽  
Conventional Drug ◽  
Repurposed Drugs

Drug repurposing is the process of finding the new uses of existing drugs. It is one of the emerging methods involved in selecting a molecule for diseases which are communicable and can spread in the general population at a faster pace. The method is selected over conventional drug discovery methods because it is a faster way to bring an existing molecule for a different disease. Ever since COVID-19 pandemic has emerged worldwide use of repurposed drugs has become an important toll to tackle this viral disease. This review is a study of the varous stargegies of drug reprposing for the treatment of COVID19.

scholarly journals A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ

2021 ◽  
Vol 22 (18) ◽  
pp. 9741
Author(s):  
Giovanni Bolcato ◽  
Eleonora Cescon ◽  
Matteo Pavan ◽  
Maicol Bissaro ◽  
Davide Bassani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Drug Candidates ◽  
Promising Target ◽  
Family Protein ◽  
Computational Workflow ◽  
Set Up ◽  
Approved Drugs

Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib. In the Kinase family, protein kinase CK1 isoform δ (CK1δ) has become a promising target in the treatment of different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition.

scholarly journals Evaluation of SARS-CoV-2 entry, inflammation and new therapeutics in human lung tissue cells

2022 ◽  
Vol 18 (1) ◽  
pp. e1010171
Author(s):  
Judith Grau-Expósito ◽  
David Perea ◽  
Marina Suppi ◽  
Núria Massana ◽  
Ander Vergara ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Inflammatory Responses ◽  
Alveolar Type ◽  
Human Lung Tissue ◽  
Physiological Models ◽  
Structural Cell ◽  
Drug Candidates ◽  
Entry Inhibitors

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.

scholarly journals Recent Advances in Hepatitis B Treatment

2021 ◽  
Vol 14 (5) ◽  
pp. 417
Author(s):  
Georgia-Myrto Prifti ◽  
Dimitrios Moianos ◽  
Erofili Giannakopoulou ◽  
Vasiliki Pardali ◽  
John E. Tavis ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Viral Entry ◽  
Antiviral Agents ◽  
Pegylated Interferon ◽  
Effective Vaccine ◽  
Immune Modulators ◽  
Treatment Regimens ◽  
Entry Inhibitors ◽  
Hepatitis B Treatment ◽  
Key Steps

Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

Application of Advanced Technologies in Natural Product Research: A Review with Special Emphasis on ADMET Profiling

2020 ◽  
Vol 21 (10) ◽  
pp. 751-767
Author(s):  
Pobitra Borah ◽  
Sangeeta Hazarika ◽  
Satyendra Deka ◽  
Katharigatta N. Venugopala ◽  
Anroop B. Nair ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Natural Product ◽  
Dynamic Range ◽  
Early Stage ◽  
Attrition Rate ◽  
Drug Candidates ◽  
Advanced Technologies ◽  
Natural Product Research ◽  
The Status ◽  
Safety Parameters

The successful conversion of natural products (NPs) into lead compounds and novel pharmacophores has emboldened the researchers to harness the drug discovery process with a lot more enthusiasm. However, forfeit of bioactive NPs resulting from an overabundance of metabolites and their wide dynamic range have created the bottleneck in NP researches. Similarly, the existence of multidimensional challenges, including the evaluation of pharmacokinetics, pharmacodynamics, and safety parameters, has been a concerning issue. Advancement of technology has brought the evolution of traditional natural product researches into the computer-based assessment exhibiting pretentious remarks about their efficiency in drug discovery. The early attention to the quality of the NPs may reduce the attrition rate of drug candidates by parallel assessment of ADMET profiling. This article reviews the status, challenges, opportunities, and integration of advanced technologies in natural product research. Indeed, emphasis will be laid on the current and futuristic direction towards the application of newer technologies in early-stage ADMET profiling of bioactive moieties from the natural sources. It can be expected that combinatorial approaches in ADMET profiling will fortify the natural product-based drug discovery in the near future.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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