COVID-19 - Coronavirus disease 2019

Lysotropic agents for the treatment of COVID-19 : azithromycin, chloroquine and hydroxychloroquine – LYSOSOMOTROP

Submission summary

Lysosomotropic agents for the treatment of COVID-19: azithromycin, chloroquine and hydroxychloroquine

Phase II clinical trials have led to the preliminary conclusion that chloroquine, hydroxychloroquine and azithromycin may reduce the viral load in patients with COVID-19, spurring the launch of multiple additional phase II trials for the chemoprevention or therapy of COVID-19. Our team has been working in the past on the cell biological effects of chloroquine and hydroxychloroquine, in particular in the context of autophagy.

Based on our experience in the elucidation of cell stress and cell death pathways, as well as on our knowledge in immunopharmacology, we propose to investigate the effect of chloroquine, hydroxychloroquine and azithromycin in multiple well-established in vitro assays that (Workpackage 1) detect and quantify cell stress at the organellar level in cells engineered to express appropriate biosensors, (Workpackage 2) elucidate cause-effect relationships between stress signals and the ignition of cell death pathways, and (Workpackage 3) determine effects on innate immune effectors such as macrophages and dendritic cells. Based on this information that will be obtained at Europe’s largest robotized cell biology screening platform, we will (Workpackage 4) determine whether similar stress/death and immune effects are induced in vivo, in mouse models, thus generating pharmacodynamics (PD) makers. Helped by our mass spectrometry metabolomics facility, we will also investigate (Workpackage 5) the organ-specific pharmacokinetics (PK) of chloroquine, hydroxychloroquine and azithromycin, focusing on the lung, as well as on the question whether aerosol delivery of these agent might yield a favorable distribution towards target organs, while reducing the abundance of the agents at undesirable sites (e.g. retina, myocardium).

We believe that mechanistic insights into the mode of action of these putative anti-COVID-19 agents may facilitate the identification of other (better?) agents sharing anti-COVID-19 activity and that a detailed knowledge on PK/PD parameters may help to optimize their clinical development.

Project coordination

Guido Kroemer (CENTRE DE RECHERCHE DES CORDELIERS)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRC CENTRE DE RECHERCHE DES CORDELIERS

Help of the ANR 30,000 euros
Beginning and duration of the scientific project: March 2020 - 18 Months

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