Biology subjects

Madrid, P.

Publications and source records attributed to Madrid, P..

4 recordsLinked to original sources

bioRxiv2020

Machine Learning Models Identify Inhibitors of SARS-CoV-2

With the ongoing SARS-CoV-2 pandemic there is an urgent need for the discovery of a treatment for the coronavirus disease (COVID-19). Drug repurposing is one of the most rapid strategies for addressing this need and numerous compounds have been selected for in vitro testing by several groups already. These have led to a growing database of molecules with in vitro activity against the virus. Machine learning models can assist drug discovery through prediction of the best compounds based on previously published data. Herein we have implemented several machine learning methods to develop predictive models from recent SARS-CoV-2 in vitro inhibition data and used them to prioritize additional FDA approved compounds for in vitro testing selected from our in-house compound library. From the compounds predicted with a Bayesian machine learning model, CPI1062 and CPI1155 showed antiviral activity in HeLa-ACE2 cell-based assays and represent potential repurposing opportunities for COVID-19. This approach can be greatly expanded to exhaustively virtually screen available molecules with predicted activity against this virus as well as a prioritization tool for SARS-CoV-2 antiviral drug discovery programs. The very latest model for SARS-CoV-2 is available at www.assaycentral.org.Competing Interest StatementSE is CEO and owner of Collaborations Pharmaceuticals, Inc. DHF, KMZ, TRL, AP are employees of Collaborations Pharmaceuticals, Inc.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Repurposing Pyramax for the Treatment of Ebola Virus Disease: Additivity of the Lysosomotropic Pyronaridine and Non-Lysosomotropic Artesunate

We have recently identified three molecules (tilorone, quinacrine and pyronaridine tetraphosphate) which all demonstrated efficacy in the mouse model of infection with mouse-adapted Ebola virus (EBOV) model of disease and had similar in vitro inhibition of an Ebola pseudovirus (VSV-EBOV-GP), suggesting they interfere with viral entry. Using a machine learning model to predict lysosomotropism these compounds were evaluated for their ability to inhibit via a lysosomotropic mechanism in vitro. We now demonstrate in vitro that pyronaridine tetraphosphate is an inhibitor of Lysotracker accumulation in lysosomes (IC50 = 0.56 M). Further, we evaluated synergy between pyronaridine and artesunate (Pyramax(R)), which are used in combination to treat malaria. Artesunate was not found to have lysosomotropic activity in vitro and the combination effect on EBOV inhibition was shown to be additive. Pyramax(R) may represent a unique example of the repurposing of a combination product for another disease.

pharmacology and toxicology↗

bioRxiv2020

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 {micro}M against three strains of EBOV and IC50 range of 1.01-2.72 {micro}M against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, which suggests significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV, providing justification for future testing in non-human primates. ImportanceThere is currently no antiviral small molecule drug approved for treating Ebola Virus infection. We have previously used machine learning models to identify new uses for approved drugs and demonstrated their activity against the Ebola virus in vitro and in vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in the guinea pig. In addition, we show that this drug is effective against multiple strains of EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These combined efforts indicate the need to further test this molecule in larger animal efficacy studies prior to clinical use in humans. These findings also may be useful for repurposing this drug for use against other viruses in future.

pharmacology and toxicology↗

bioRxiv2020

Tilorone: A Broad-Spectrum Antiviral For Emerging Viruses

Tilorone is a 50-year-old synthetic small-molecule compound with antiviral activity that is proposed to induce interferon after oral administration. This drug is used as a broad-spectrum antiviral in several countries of the Russian Federation. We have recently described activity in vitro and in vivo against the Ebola Virus. After a broad screening of additional viruses, we now describe in vitro activity against Chikungunya virus (CHIK) and Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV).

pharmacology and toxicology↗