Drug repurposing screen IDs hep C antivirals as inhibitors of Covid protease

Jeremy D. Baker, Rikki L. Uhrich, Gerald C. Kraemer, Jason E. Love, View ORCID ProfileBrian C. Kraemer

doi: https://doi.org/10.1101/2020.07.10.197889

This article is a preprint and has not been certified by peer review [what does this mean?].

• Abstract
• Full Text
• Info/History
• Metrics
• Preview PDF

Abstract

The SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic ^1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly. The overall case fatality rate for COVID-19 is estimated to be ∼2.3% overall ³ and 32.3% in hospitalized patients age 70-79 years ⁴. Therapeutic options for treating the underlying viremia in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ∼6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found ∼50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 μM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including Boceprevir (IC50=0.95 μM), Ciluprevir (20.77μM). Narlaprevir (IC50=1.10μM), and Telaprevir (15.25μM). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2020.07.10.197889v1

The link between Vitamin D and Covid-19: distinguishing facts from fiction

Peter Bergman  ¹

Affiliations Expand

• PMID: 32652766
• DOI: 10.1111/joim.13158

Abstract

Vitamin D is produced in the skin under the influence of UVB-light from the sun or obtained via the diet by eating fatty fish, enriched dairy products or supplements. Vitamin D is known to support a healthy bone and severe deficiency may lead to osteomalacia or the rickets, which still occur in poor areas of the world. In addition, vitamin D support key functions in many organs, including the brain, muscle and the immune systems (Holick, 2007). In fact, the vitamin D receptor (VDR) is expressed in most cell types and may activate somewhere between 200-500 genes, many related to the immune system.

https://pubmed.ncbi.nlm.nih.gov/32652766/

INmune lead drug shows encouraging action in early-stage Alzheimer’s study

INmune Bio (NASDAQ:INMB) soars 86% after hours in reaction to positive interim data from a Phase 1b study evaluating lead drug XPro1595 in Alzheimer’s disease (AD) patients. Treatment with the next-generation tumor necrosis factor (TNF) inhibitor demonstrating decreased neuroinflammation in AD patients via a decrease in white matter water, a biomarker of brain inflammation measured by MRI scan.

The company compared biomarker data obtained from six patients treated with XPro1595 for 12 weeks to data from 25 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

Whole brain inflammation increased by 5.1% in ADNI patients compared to an increase of 1.7% and a decrease of 2.3% in patients treated weekly with 0.3mg/kg and 1.0mg/kg, respectively, of XPro1595.

A more detailed analysis showed a 40.6% reduction in neuroinflammation in the Arcuate Fasciculus (major white matter anterior/posterior tract important for language and short-term memory). The ADNI cohort had a 4.6% increase in Arcuate Fasciculus neuroinflammation.

INmune will host a key opinion leader event at 8 a.m. ET tomorrow.

https://seekingalpha.com/news/3590797-inmune-lead-drug-shows-encouraging-action-in-early-stage-alzheimers-study

Vaccine production to begin this summer – Administration official

A senior official administration official says production of a potential coronavirus vaccine is expected to begin before the end of the summer.

The hope is to be able to deliver 300M doses by early 2021, and the process to begin manufacturing is underway even though no one is sure which vaccine will work, if any.

The Nasdaq reversed an early 1.5% advance to close down 2.1%. The S&P 500 also negated a big gain to close down 0.95%.

Moderna (NASDAQ:MRNA) is ahead 2.35% in after hours action. Vanda Pharma (NASDAQ:VNDA) +9.9%.

https://seekingalpha.com/news/3590819-vaccine-production-to-begin-this-summer-administration-official

BioSig up on start of mid-stage study of merimipodib in COVID-19

BioSig Technologies (BSGM +7.8%) subsidiary ViralClear Pharmaceuticals announces the start of enrollment in a Phase 2 clinical trial evaluating antiviral merimipodib, combined with Gilead Sciences’ (GILD +2.3%) remdesivir, in adult COVID-19 patients compared to remdesivir + placebo.

The primary endpoints are safety and the number of subjects not hospitalized or if hospitalized, free of respiratory failure, through day 28.

https://seekingalpha.com/news/3590719-biosig-up-8-on-start-of-mid-stage-study-of-merimipodib-in-covidminus-19

Arcutis initiates enrollment in mid-stage study of ARQ-252 in hand eczema

Arcutis Biotherapeutics (ARQT -2.8%) initiates enrollment in the Phase 2b portion of Phase 1/2b study of ARQ-252, selective topical small molecule Janus kinase type 1 inhibitor, in chronic hand eczema.

The Phase 2b portion of the study will assess the safety and efficacy of ARQ-252 cream 0.1% once daily and ARQ-252 cream 0.3% once daily or twice daily versus vehicle applied once daily or twice daily for 12 weeks to patients with chronic hand eczema.

The Company expects topline data from the trial in 2H 2021.

https://seekingalpha.com/news/3590688-arcutis-initiates-enrollment-in-mid-stage-study-of-arqminus-252-in-hand-eczema

Meridian Bio launches antibody pair for development of rapid COVID-19 tests

Meridian Bioscience (VIVO +2.8%) launches a high-sensitivity SARS-CoV-2 nucleocapsid monoclonal antibody pair that can be used to develop a rapid lateral flow COVID-19 antigen test.

EVP, Life Science Lourdes Weltzien, Ph.D., says, “There are many highly sensitive molecular tests available that can diagnose an infection early, but they require processing in a laboratory and take time to report a result.  We now provide an antibody pair that can be used to create fast, point-of-care assays, capable of delivering results in minutes rather than hours.”

https://seekingalpha.com/news/3590703-meridian-bioplus-3-launches-antibody-pair-for-development-of-rapid-covidminus-19-tests