Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is localized in endosomes and lysosomes with a polarized substrate transport from the cell cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and both basic drugs, which are potent lysosomotropic compounds, will become protonated and trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal enzyme activities responsible in virus entry and replication cycle. Based on these considerations, we hypothesize that ABCB1 could be a possible enhancer by confining azithromycin more extensively than expected when the trapping is solely dependent on the passive diffusion. This additional mechanism may therefore explain the synergistic effect when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus clearance and better clinical benefit, when compared to monotherapy with hydroxychloroquine alone.
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PMID:Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy. 3253 63

Coronavirus Disease 2019 (COVID-19) has infected more than thirty five million people worldwide and caused nearly 1 million deaths as of October 2020. The microorganism causing COVID-19 was named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or 2019-nCoV). The aim of this study was to investigate the interactions of twenty-three phytochemicals belonging to different flavonoid subgroups with the receptor binding domain (RBD) of the spike glycoprotein of 2019-nCoV, and cellular proteases [transmembrane serine protease 2 (TMPRSS2), cathepsin B and L (CatB/L)]. The compounds interacted more strongly with CatB and CatL than with the other proteins. Van der Waals and hydrogen bonds played an important role in the receptor-ligand interactions. As a result of RBCI (relative binding capacity index) analysis conducted to rank flavonoids in terms of their interactions with the target proteins, (-)-epicatechin gallate interacted strongly with all the proteins studied. The results obtained from molecular dynamics and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods also supported this data. According to Lipinski's rule of five, (-)-epicatechin gallate showed drug-likeness properties. Although this molecule is not capable of crossing the blood-brain barrier (BBB), it was concluded that (-)-epicatechin gallate can be evaluated as a candidate molecule in drug development studies against 2019-nCoV since it was not the substrate of P-gp (P-glycoprotein), did not inhibit any of the cytochrome Ps, and did not show AMES toxicity or hepatotoxicity on eukaryotic cells.
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PMID:In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties. 3311 22