Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

Modeling of SARS-CoV-2 treatment effects for informed drug repurposing

10.21203/rs.3.rs-153281/v2 ◽

2021 ◽

Author(s):

Charlotte Kern ◽

Verena Schöning ◽

Carlos Chaccour ◽

Felix Hammann

Keyword(s):

Drug Repurposing ◽

Antiviral Effect ◽

Drug Candidate ◽

Appreciable Effect ◽

Viral Kinetics ◽

Future Drug ◽

Dosing Regimens ◽

Clinical Trial Results

Abstract Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide.We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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Modeling of SARS-CoV-2 treatment effects for informed drug repurposing

10.21203/rs.3.rs-153281/v3 ◽

2021 ◽

Author(s):

Charlotte Kern ◽

Verena Schöning ◽

Carlos Chaccour ◽

Felix Hammann

Keyword(s):

Drug Repurposing ◽

Antiviral Effect ◽

Drug Candidate ◽

Appreciable Effect ◽

Viral Kinetics ◽

Future Drug ◽

Dosing Regimens ◽

Clinical Trial Results

Abstract Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide.We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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Modeling of SARS-CoV-2 treatment effects for informed drug repurposing

10.21203/rs.3.rs-153281/v1 ◽

2021 ◽

Author(s):

Charlotte Kern ◽

Verena Schöning ◽

Carlos Chaccour ◽

Felix Hammann

Keyword(s):

Drug Repurposing ◽

Antiviral Effect ◽

Drug Candidate ◽

Appreciable Effect ◽

Viral Kinetics ◽

Future Drug ◽

Dosing Regimens ◽

Clinical Trial Results

Abstract Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide.We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

10.1101/2020.06.30.180380 ◽

2020 ◽

Cited By ~ 1

Author(s):

Maria Alimova ◽

Eriene-Heidi Sidhom ◽

Abhigyan Satyam ◽

Moran Dvela-Levitt ◽

Michelle Melanson ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Drug Repurposing ◽

Lung Epithelial Cells ◽

Drug Candidate ◽

Mucin 1 ◽

Standing Up

SummaryDrug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

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A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern

10.1101/2021.08.08.455562 ◽

2021 ◽

Author(s):

Teresa R. Wagner ◽

Daniel Schnepf ◽

Julius Beer ◽

Karin Klingel ◽

Natalia Ruetalo ◽

...

Keyword(s):

Lethal Dose ◽

Survival Rates ◽

Drug Candidate ◽

Lethal Challenge ◽

Drug Candidates ◽

High Affinity ◽

Neutralizing Capacity ◽

Future Drug

The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.

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In-silico studies of Riparin B in the design of drugs: Physicochemical, pharmacokinetic and pharmacodynamic parameters

10.1101/2020.04.24.059626 ◽

2020 ◽

Author(s):

Aldenora Maria Ximenes Rodrigues ◽

Rayla Kelly Magalhães Costa ◽

Ranyelison Silva Machado ◽

Stanley Juan Chavez Gutierrez ◽

Francisco das Chagas Alves Lima ◽

...

Keyword(s):

In Silico ◽

Computational Prediction ◽

Drug Candidate ◽

Pharmacokinetic Parameters ◽

Synthetic Analog ◽

In Silico Studies ◽

Future Drug ◽

On Line

AbstractThe process involved in the research, discovery and development of drugs is characterized by high extensive and complex cost linked to scientific and technological innovations, and it is necessary to study and verify the progress of research carried out in the field that results in patent applications. Aniba riparia (Nees) Mez is a plant species often used for therapeutic purposes, where its pharmacological properties are associated to the presence of alkaloids called riparins. 5 synthetic analog compounds (riparins A, B, C, D, E and F) were developed from natural riparins. These molecules, natural and synthetic, showed several pharmacological activities in tests performed in vitro and in vivo, highlighting the Central Nervous System (CNS). The objective of this work was to evaluate the physical-chemical, pharmacokinetic parameters (absorption, distribution, metabolism, excretion and toxicity) and pharmacodynamic parameters (bioactivity and adverse reactions) of Riparin B by means of in silico computational prediction. Online software such as Pre-ADMET, SwissADME, Molinspiration and PASS on line were used for the analysis. Riparin B fits the characteristics of druglikeness, pharmacokinetic properties appropriate to the predicted patterns and activities within the scope for the treatment of AD, demonstrating a possible potential in the inhibition of AChE. Therefore, in silico results allow us to conclude that riparin B is predicted to be a potential future drug candidate, especially via oral administration, due to its relevant Drug-likeness profile, bioavailability, excellent liposolubility and adequate pharmacokinetics, including at the level of CNS, penetrating the blood-brain barrier.

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Metacytofilin Is a Potent Therapeutic Drug Candidate for Toxoplasmosis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz501 ◽

2019 ◽

Cited By ~ 2

Author(s):

Arpron Leesombun ◽

Masatomi Iijima ◽

Kousuke Umeda ◽

Daisuke Kondoh ◽

Baldorj Pagmadulam ◽

...

Keyword(s):

Rna Degradation ◽

Drug Candidate ◽

Therapeutic Drug ◽

Ocular Manifestations ◽

Future Drug ◽

Pregnant Mice ◽

Infected Cells ◽

Strong Candidate

Abstract Background Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound. Methods Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. Results In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii–infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. Conclusions With its potent anti–T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.

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Connecting Hydroxychloroquine In Vitro Antiviral Activity to In Vivo Concentration for Prediction of Antiviral Effect: A Critical Step in Treating Patients With Coronavirus Disease 2019

Clinical Infectious Diseases ◽

10.1093/cid/ciaa623 ◽

2020 ◽

Cited By ~ 22

Author(s):

Jianghong Fan ◽

Xinyuan Zhang ◽

Jiang Liu ◽

Yuching Yang ◽

Nan Zheng ◽

...

Keyword(s):

Antiviral Activity ◽

Tissue Concentration ◽

Antiviral Effect ◽

Effective Concentration ◽

Critical Step ◽

Dosing Regimens ◽

Free Plasma

Abstract Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro 50%/90% maximal effective concentration values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.

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Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190318120103 ◽

2019 ◽

Vol 20 (4) ◽

pp. 285-292 ◽

Cited By ~ 5

Author(s):

Abdullah M. Alnuqaydan ◽

Bilal Rah

Keyword(s):

Medicinal Plant ◽

Biological Activities ◽

Wide Spectrum ◽

Biological Properties ◽

In Vivo Model ◽

Drug Candidate ◽

Phytochemical Analysis ◽

Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

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