key: cord-0966122-1t4ykc01
authors: Altay, Ozlem; Mohammadi, Elyas; Lam, Simon; Turkez, Hasan; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Mardinoglu, Adil
title: Current status of COVID-19 therapies and drug repositioning applications
date: 2020-06-20
journal: iScience
DOI: 10.1016/j.isci.2020.101303
sha: 89c2a3d86ab07b689701b170d484e33c33f44176
doc_id: 966122
cord_uid: 1t4ykc01

Summary The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2.

Over the past few centuries, outbreaks caused by bacteria like Yersinia pestis and Vibrio cholerae (the 29 causative agents of plague and cholera, respectively(Cohn and Kutalek, 2016; Pechous et al., 2016) and 30

also by viral infectious agents such as influenza viruses, ebolaviruses, SARS-CoV-1, MERS-CoV, the 31

Zika virus, and lately, SARS-CoV-2, have undermined public trust in the ability for modern science to 32 predict and prevent global pandemic threats. Accordingly, studying historical epidemics can help us 33 identify patterns of viral outbreaks and design a plan to prepare for next pandemic. provide a better picture of statistics related to asymptomatic infections for epidemiologic analysis. 59

The phylogeny, virology, and epidemiology of SARS-CoV-2 is being studied extensively. At the genome 60 level, SARS-CoV-2 has 79·5% homology to SARS CoV- CoV-2 and other coronaviruses, and its relative ease of sample acquisition and study, it has been widely 75 accepted that drug repositioning is a promising approach to make available an effective, safety-assured 76 treatment in a timely manner. In this review, we summarize diagnosis approaches, risk groups, available 77 treatment options, and drug repositioning studies related to COVID-19. 78

Prior to efficient treatment, precise diagnosis and classification of patients based on disease severity and 80

their probable vulnerability to COVID-19 is crucial. Diagnosis has several steps that can be prioritized 81

based on the provision of facilities during an outbreak. Generally, evaluation of symptoms and particular 82 laboratory features that are associated with worse cases come first. Considering antihypertensive medications, there are advocates for both use and cessation of consumption. 108

It is still unclear whether the high mortality rate of patients with hypertension comorbidity is due to the 109 pathology of disorder or the treatment used to cure it such as angiotensin-converting enzyme inhibitors 110

(ACEIs) and angiotensin receptor blockers (ARBs). ACE2 has been shown to be a co-receptor for viral 111 entry and pathogenesis of SARS-CoV. (Li et al., 2003) There is considerable evidence which shows the 112 escalated expression level of ACE2 in the heart, brain, and even in urine after treatment with ARBs; 113 however, there is limited evidence showing changes in serum or pulmonary ACE2 levels. (Patel and 114 Verma, 2020; Zhang et al., 2020c) In addition, serological, radiological, and histo-morphological 115 similarities of COVID-19-associated acute respiratory distress syndrome (ARDS) and connective tissue 116 disease (CTD-ILD) propose the postulation of triggering or simulating a form of organ-specific 117 autoimmunity in predisposed patients. Also, some patients showed high titer antiphospholipid antibodies, 118

including anticardiolipin antibodies and anti-β2 glycoprotein antibodies. (Zhang et al., 2020d) The 119

immunosuppressive therapy in identified patients with autoantibodies may prevent the development of 120 respiratory failure. 121

With regard to treatment, immunological and pharmaceutical investigations are still ongoing. No specific 124 therapies for COVID-19 is approved by U.S. Food and Drug Administration (FDA) so far but many 125 previously approved drugs, as an efficient approach to drug discovery named drug repurposing, is being 126 tested on COVID-19. At the time of writing, 1137 interventional studies have been registered in 127

ClinicalTrials.gov (https://clinicaltrials.gov/) related to COVID-19 and this number is increasing 128

progressively (Table S1 ). In particular, the ongoing clinical trials sponsored by WHO named Solidarity 129

will compare different treatment options, namely remdesivir; lopinavir/ritonavir dual treatment; 130 lopinavir/ritonavir dual treatment with interferon beta 1-alpha; and chloroquine or hydroxychloroquine 131 (paused temporarily due to the concerns raised about the safety of the drug) against standard of care. As 132

of May 10 th, 2020, more than 100 countries have been confirmed to contribute in this investigation. 133

The interventional drugs in clinical trials can be classified based on their nature and complementary 134 effect. In this regard, antivirals, antiparasitic drugs, immunosuppressors, immunomodulators, some well-135 known drugs, and nutritional drugs, in addition to combination therapies are considered on ongoing 136 studies for treatment, supportive care or prevention. One can barely see the same mechanism of action 137

inside and outside each group (Table 1 ) but many drugs are discovered for a specific disease and 138

repurposed later for another disorder. Figure 2 illustrates a general path which is being traversed by 139 clinicians these days although, the results may not be desirable in some cases due to the emergent nature 140

of SARS-CoV-2. In-silico drug repurposing methodologies have accelerated the studies in drug discovery through the use 250 of data mining approaches, bioinformatics techniques, and predictive models for determining the efficacy 251 and safety of the drugs. However, there is still a long way to reach the high success rates with repurposed 252 drugs (e.g. repurposed candidates succeeded 9-67% -depending on the similarity between indicated and 253

repurposed therapeutic areas -and the novel molecular entity success rate is ~ 10% and reduce the possibility of hypothesis risk will be essential to increase the success rate of repurposed 266 drugs in the product development process. A computation-based methodology, namely Viral-Track, applied to bronchoalveolar lavage samples from 303

severe and mild COVID-19 patients unveils a remarkable impact of the virus on the immune system of 304

severe patients compared to mild cases, including replacement of the tissue resident alveolar macrophages 305

with recruited inflammatory monocytes, neutrophils, and macrophages and an altered CD8+ T cell 306 cytotoxic response.(Bost et al., 2020) Further efforts on large-scale datasets will lead to reveal many 307 mechanistic aspects of viral infections yet to be resolved and will help to develop more efficient therapy 308 strategies. 309

Due to urgent need, we posit that drug repurposing is the leading method for drug discovery against 311

COVID-19, whether through wet lab techniques and/or system biology approaches. Available clinical 312 trials at both ClinicalTrials.gov (https://clinicaltrials.gov/) and WHO Solidarity includes the investigation 313 of previously approved drugs for different indications. Taking into account that in the past two decades 314 three coronaviruses emerged from animal reservoirs (the virus family which used to cause mild to 315 moderate upper-respiratory tract illnesses) and each one of them was cause of global concern, a common 316 treatment may prevent coronavirus to become another lethal annual re-occurrent threat on top of seasonal 317

influenza. 

Data for this review were identified by searches of PubMed, Google Scholar, and references from 329 relevant articles using the search terms "SARS-CoV-2", "COVID-19", "drug repurposing", "antiviral 330 therapy", "clinical trials", "COVID-19 therapy", and "pandemi". Only articles published in English were 331

included. 332

This work was supported by Knut and Alice Wallenberg Foundation. The funders had no role in study 334

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Jakafi ® , Jakavi ® JAK inhibition Rheumatoid arthritis 

Plague outbreaks era