Focusing on the Unfolded Protein Response and Autophagy Related Pathways to Reposition Common Approved Drugs against COVID-19

Abstract

More than 179,000 individuals have fallen ill of the Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus, which first emerged in China less than four months ago in December 2019. As of today, there exist no approved treatments against COVID-19. Vaccines are being developed, but they will take time, at least one year, to reach the population. Drug repositioning represents a fast track because already approved medicines have been broadly tested through multiple trials. We developed a repositioning strategy that mostly leads to candidates that are commonly used. The advantages are that they will facilitate proof of concept in humans through a “real-world evidence” approach and should be rapidly available to the population. We focus on the established research results that the unfolded protein response (UPR) and autophagy pathways of the host cells are essential to the life cycle of previously known coronaviruses. We performed the relevant bioinformatics analysis to understand and confirm if SARS-CoV-2 may interact with these druggable pathways. Based on these considerations, we prioritized two additional druggable pathways, which are important to the viral life cycle and tightly connected to UPR/autophagy signaling: the mitochondrial permeability transition pores (MPTP) and NLRP-3 inflammasome pathways. These four important pathways are perturbed in most major common diseases and have therefore been targeted by numerous broadly prescribed drugs. We have identified 97 approved drugs that are known to modulate these four identified pathways, and which represent, therefore, interesting repositioning candidates. Although it is indisputable that these drugs should never be used for immediate self-medication against COVID-19, we notice that some of them could also be prescribed to individuals who have COVID-19 comorbidities (e.g., hypertension). It is debated if these comorbidities are linked to the pathology itself (e.g., hypertension) or the drugs used to treat the pathology (e.g., sartans). Therefore, relevant preclinical tests and massive electronic health records (i.e., real-world evidence) must be used to pre-screen them and check the COVID-19 prognosis of individuals taking these drugs.

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

“…Other studies have pointed out that drug repurposing may identify approved drugs that could be useful for the treatment of this disease including, notably, chloroquine, hydroxychloroquine and azithromycin, as well as anti-diabetics such as metformin, angiotensin receptor inhibitors such as sartans, or statins such as simvastatin [11]. In addition, chloroquine has demonstrated its efficacy in Chinese COVID-19 patients in clinical trials by reducing fever, improving CT imaging, and delaying disease progression [12][13][14], leading Chinese experts to recommend chloroquine-based treatment (500 mg twice per day for ten days) as a first line-treatment for mild, moderate and severe cases of COVID-19 [15].…”

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

“…N-Desmethyl-4-hydroxy tamoxifen beta-D-glucuronide (E/Z Mixture) has also been identi ed as a strong binding ligand. Tamoxifen has also been proposed as an anti-COVID-19 drug as it can induce autophagy associated with the unfolded protein response to kill infected cells and thus contain the virus 80 . Octane-1,3,5,7-tetracarboxylic acid B belongs to the class of zinc ion binding compounds that target Carboxypeptidase A1.…”

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

“…N-Desmethyl-4-hydroxy tamoxifen beta-D-glucuronide (E/Z Mixture) has also been identi ed as a strong binding ligand. Tamoxifen has also been proposed as an anti-COVID19 drug as it can induce autophagy associated with the unfolded protein response to kill infected cells and thus contain the virus 82 . Octane-1,3,5,7-tetracarboxylic acid B belongs to the class of zinc ion binding compounds that target Carboxypeptidase A1.…”