scholarly journals Challenges in Chagas Disease Drug Development

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2799 ◽  
Author(s):  
Amanda F. Francisco ◽  
Shiromani Jayawardhana ◽  
Francisco Olmo ◽  
Michael D. Lewis ◽  
Shane R. Wilkinson ◽  
...  
Keyword(s):  
Drug Development ◽  
Chagas Disease ◽  
High Throughput Screening ◽  
Public Health Problem ◽  
Drug Repurposing ◽  
Current Status ◽  
Laboratory Research ◽  
Important Public Health Problem ◽  
Treatment Regimens ◽  
Compound Libraries

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process.

scholarly journals Identification of SARS-CoV-2 Receptor Binding Inhibitors by In Vitro Screening of Drug Libraries

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3213
Author(s):  
Alon Ben David ◽  
Eran Diamant ◽  
Eyal Dor ◽  
Ada Barnea ◽  
Niva Natan ◽  
...  
Keyword(s):  
Receptor Binding ◽  
High Throughput Screening ◽  
Cell Attachment ◽  
Drug Repurposing ◽  
Heparin Sodium ◽  
Compound Libraries ◽  
Global Pandemic ◽  
Ic50 Values ◽  
Binding Inhibitors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC®1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors.

E-Ophthalmology in the Diagnosis and Follow-Up of Chronic Glaucoma

2013 ◽  
pp. 88-108 ◽  
Author(s):  
Jose Andonegui ◽  
Aitor Eguzkiza ◽  
Mikel Auzmendi ◽  
Luis Serrano ◽  
Ane Zurutuza ◽  
...  
Keyword(s):  
Public Health ◽  
Intraocular Pressure ◽  
Visual Fields ◽  
Public Health Problem ◽  
Current Status ◽  
Future Trends ◽  
Important Public Health Problem ◽  
Important Public Health ◽  
Chronic Glaucoma

e-Ophthalmology is the use of information and telecommunications technologies to provide or support a group of activities related to ophthalmic care. Chronic glaucoma is an ocular disease characterized by optic neuropathy that leads to progressive loss of the visual fields and often is associated with elevated intraocular pressure levels. Glaucoma is an important public health problem because it is one of the main causes of blindness worldwide and generates an important demand for ophthalmologic consultations. The aim of this chapter is to discuss the application e-Ophthalmology-based models in the diagnosis and follow-up of chronic glaucoma. The authors describe the current status of the use of e-Ophthalmology-based models in the screening and follow-up of chronic glaucoma, the main advantages of these models, the technologic requirements for their implementation, and future trends in this field.

Antileishmanial Drug Development: A Review of Modern Molecular Chemical Tools and Research Strategies

2020 ◽  
Vol 28 ◽  
Author(s):  
Pavan K. Mantravadi ◽  
Anutthaman Parthasarathy ◽  
Karunakaran Kalesh
Keyword(s):  
Visceral Leishmaniasis ◽  
Drug Development ◽  
High Throughput Screening ◽  
Complex Disease ◽  
Geographic Location ◽  
Sequence Information ◽  
Research Strategies ◽  
Chemical Genetic ◽  
Compound Libraries ◽  
Antileishmanial Drug

: Leishmaniasis, a complex disease caused by at least 20 species of unicellular parasites of the genus Leishmania, disproportionately affects impoverished regions of about 90 tropical and sub-tropical countries. Currently available antileishmanial therapies, particularly for the visceral leishmaniasis, are severely limited, with treatment outcome depending on many factors including the immune status of the patient, comorbidities, malnutrition, and socio-economic conditions in the patient’s geographic location. There is an urgent need for new therapeutics, particularly new effective oral drugs, for visceral leishmaniasis. Despite the availability of the Leishmania genome sequence information and significant research into the biology of the parasites, antileishmanial drug development is hampered by the lack of knowledge about druggable targets in the parasite and difficulties in identifying the molecular targets of compounds that show activity. In this context, we analyse recent progress in antileishmanial drug development programmes, which take advantage of different powerful approaches such as high-throughput screening of compound libraries, recent developments in genetic methods for assessing essentiality of parasite genes and, chemical, genetic and proteomics-based target discovery and target validation methods.

Coronavirus Disease 2019: Virology and Drug Targets

2020 ◽  
Vol 20 ◽  
Author(s):  
Praveen Thaggikuppe Krishnamurthy
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Structural Proteins ◽  
Current Status ◽  
Approved Drugs ◽  
Viral Target ◽  
Fda Approved Drugs

: The Coronavirus Disease 2019, a pandemic caused by novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is seriously affecting global health and the economy. As the vaccine development takes time, the current research is focused on repurposing FDA approved drugs against the viral target proteins. This review discusses the current understanding of SARS-CoV-2 virology, its target structural proteins (S- glycoprotein), non-structural proteins (3- chymotrypsin-like protease, papain-like protease, RNA-dependent RNA polymerase, and helicase) and accessory proteins, drug discovery strategies (drug repurposing, artificial intelligence, and high-throughput screening), and the current status of antiviral drug development.

The Salmonella Problem: Current Status and Future Direction1

1982 ◽  
Vol 45 (7) ◽  
pp. 661-666 ◽  
Author(s):  
JOHN H. SILLIKER
Keyword(s):  
Animal Feed ◽  
Public Health Problem ◽  
Human Infection ◽  
School Level ◽  
Poultry Meat ◽  
Current Status ◽  
High School Level ◽  
Important Public Health Problem ◽  
Source Of Infection ◽  
Human Salmonellosis

Human salmonellosis continues to be an important public health problem. Consumer mishandling of poultry, meat and dairy products is the most frequent cause of outbreaks. Attempts to educate consumers in proper food handling practices have had disappointing results. Denmark has an intensive program directed towards students in the 7, 8, 9 and 10th grades. Canada is contemplating a similar program for students at the high school level. Similar efforts do not exist in the U.S. Contaminated animal feed continues to be an important source of infection to livestock. The recent rise in the importance of Salmonella agona and Salmonella hadar illustrates again the important chain leading from feed contamination to livestock infection to human infection. Scandinavian countries have intensive programs directed toward control of Salmonella in domestic meat animals. Indications are that this has decreased the incidence of Salmonella in livestock and that concurrently there has been a decreased incidence of human salmonellosis in these countries. The Nurmi concept, involving oral administration of the gastrointestinal flora of adult birds into newly hatched chicks and poults, shows promise as a practical and economical approach to reducing the incidence of salmonellae in poultry.

scholarly journals High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity

2021 ◽  
Author(s):  
Ryan Choi ◽  
Mowei Zhou ◽  
Roger Shek ◽  
Jesse W. Wilson ◽  
Logan Tillery ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Nonstructural Protein ◽  
Unmet Need ◽  
Drug Repurposing ◽  
Great Promise ◽  
Compound Libraries ◽  
Global Pandemic ◽  
Essential Enzyme

AbstractSARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 μM range in vitro. Furthermore, Exebryl-1, a β-amyloid anti-aggregation molecule for Alzheimer’s therapy, was shown to have antiviral activity between 10 to 66 μM, in VERO, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.Author summaryDrugs to treat COVID-19 are urgently needed. To address this, we searched libraries of drugs and drug-like molecules for inhibitors of an essential enzyme of the virus that causes COVID-19, SARS-CoV-2 nonstructural protein (nsp)15. We found several molecules that inhibited the nsp15 enzyme function and one was shown to be active in inhibiting the SARS-CoV-2 virus. This demonstrates that searching for SARS-CoV-2 nsp15 inhibitors can lead inhibitors of SARS-CoV-2, and thus therapeutics for COVID-19. We are currently working to see if these inhibitors could be turned into a drug to treat COVID-19.

scholarly journals Sudden Cardiac Death Risk Stratification and Prevention in Chagas Disease: A Non-systematic Review of the Literature

2020 ◽  
Vol 9 (4) ◽  
pp. 175-181
Author(s):  
Roberto Keegan ◽  
Cynthia Yeung ◽  
Adrian Baranchuk
Keyword(s):  
Sudden Cardiac Death ◽  
Risk Stratification ◽  
Chagas Disease ◽  
Cardiac Death ◽  
Public Health Problem ◽  
Left Ventricular ◽  
Important Public Health Problem ◽  
Chagas Heart Disease ◽  
Sudden Cardiac Death Risk ◽  
Risk Stratification Score

Chagas disease is an important public health problem in Latin America. However, migration and globalisation have resulted in the increased presence of Chagas disease worldwide. Sudden cardiac death is the leading cause of death in people with Chagas disease, most often due to ventricular fibrillation. Although more common in patients with documented ventricular arrhythmias, sudden cardiac death can also be the first manifestation of Chagas disease in patients with no previous symptoms or known heart failure. Major predictors of sudden cardiac death include cardiac arrest, sustained and non-sustained ventricular tachycardia, left ventricular dysfunction, syncope and bradycardia. The authors review the predictors and risk stratification score developed by Rassi et al. for death in Chagas heart disease. They also discuss the evidence for anti-arrhythmic drugs, catheter ablation, ICDs and pacemakers for the prevention of sudden cardiac death in these patients. Given the widespread global burden, understanding the risk stratification and prevention of sudden cardiac death in Chagas disease is of timely concern.

scholarly journals High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV-2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250019
Author(s):  
Ryan Choi ◽  
Mowei Zhou ◽  
Roger Shek ◽  
Jesse W. Wilson ◽  
Logan Tillery ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Unmet Need ◽  
Drug Repurposing ◽  
Great Promise ◽  
Compound Libraries ◽  
Global Pandemic ◽  
Dependent Endonuclease ◽  
High Throughput Assay

SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1–20 μM range in vitro. Furthermore, Exebryl-1, a ß-amyloid anti-aggregation molecule for Alzheimer’s therapy, was shown to have antiviral activity between 10 to 66 μM, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.

scholarly journals Artificial Intelligence-driven drug repurposing and structural biology for SARS-CoV-2

2021 ◽  
Author(s):  
Kartikay Prasad ◽  
Vijay Kumar
Keyword(s):  
Artificial Intelligence ◽  
Drug Development ◽  
Structural Biology ◽  
Drug Repurposing ◽  
Current Status ◽  
Full Potential ◽  
Potential Applications ◽  
Infectious Proteins ◽  
Applications Of Ai

Abstract It has been said that COVID-19 is a generational challenge in many ways. But, at the same time, it becomes a catalyst for collective action, innovation, and discovery. Realizing the full potential of artificial intelligence (AI) for structure determination of unknown proteins and drug discovery are some of these innovations. Potential applications of AI include predicting the structure of the infectious proteins, identifying drugs that may be effective in targeting these proteins, and proposing new chemical compounds for further testing as potential drugs. AI and machine learning (ML) allow for rapid drug development including repurposing existing drugs. Algorithms were used to search for novel or approved antiviral drugs capable of inhibiting SARS-CoV-2. This paper presents a survey of AI and ML methods being used in various biochemistry of SARS-CoV-2, from structure to drug development, in the fight against the deadly COVID-19 pandemic. It is envisioned that this study will provide AI/ML researchers and the wider community an overview of the current status of AI applications particularly in structural biology, drug repurposing and development and motivate researchers in harnessing AI potentials in the fight against COVID-19.

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