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1.
J Pharmacol Exp Ther ; 2020 Jul 28.
Article in English | MEDLINE | ID: covidwho-691116

ABSTRACT

COVID-19 is a novel disease caused by the SARS-CoV-2 virus that was first detected in December of 2019 in Wuhan, China and has rapidly spread worldwide. The search for a suitable vaccine as well as effective therapeutics for the treatment of COVID-19 is underway. Drug repurposing screens provide a useful and effective solution for identifying potential therapeutics against SARS-CoV-2. For example, the experimental drug remdesivir, originally developed for Ebola virus infections, has been approved by the FDA as an emergency use treatment for COVID-19. However, the efficacy and toxicity of this drug needs further improvements. In this review, we discuss recent findings on the pathology of coronaviruses and the drug targets for the treatment of COVID-19. Both SARS-CoV-2 specific inhibitors and broad-spectrum anti-coronavirus drugs against SARS-CoV, MERS-CoV, and SARS-CoV-2 will be valuable additions to the anti-SARS-CoV-2 armament. A multi-target treatment approach with synergistic drug combinations containing different mechanisms of action may be a practical therapeutic strategy for the treatment of severe COVID-19. Significance Statement Understanding the biology and pathology of RNA viruses is critical to accomplish the challenging task of developing vaccines and therapeutics against SARS-CoV-2. This review highlights the anti-SARS-CoV-2 drug targets and therapeutic development strategies for COVID-19 treatment.

2.
Biochem Mol Biol Educ ; 2020 Aug 01.
Article in English | MEDLINE | ID: covidwho-690730

ABSTRACT

The use of online platform to conduct teaching and learning activities has becoming a new norm for teachers and students during this COVID-19 outbreak. In this commentary, we share our experiences of using online conferencing platform to promote active and interactive learning among students. We also suggest approaches that teachers can use to design their teaching and learning activities by employing reciprocal teaching as a way to engage students online instead of using the platform for didactic teaching by the teacher. The proposed strategy is applicable and transferable to other domains.

3.
J Proteome Res ; 19(4): 1351-1360, 2020 04 03.
Article in English | MEDLINE | ID: covidwho-688546

ABSTRACT

As the infection of 2019-nCoV coronavirus is quickly developing into a global pneumonia epidemic, the careful analysis of its transmission and cellular mechanisms is sorely needed. In this Communication, we first analyzed two recent studies that concluded that snakes are the intermediate hosts of 2019-nCoV and that the 2019-nCoV spike protein insertions share a unique similarity to HIV-1. However, the reimplementation of the analyses, built on larger scale data sets using state-of-the-art bioinformatics methods and databases, presents clear evidence that rebuts these conclusions. Next, using metagenomic samples from Manis javanica, we assembled a draft genome of the 2019-nCoV-like coronavirus, which shows 73% coverage and 91% sequence identity to the 2019-nCoV genome. In particular, the alignments of the spike surface glycoprotein receptor binding domain revealed four times more variations in the bat coronavirus RaTG13 than in the Manis coronavirus compared with 2019-nCoV, suggesting the pangolin as a missing link in the transmission of 2019-nCoV from bats to human.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Genome, Viral/genetics , Host-Pathogen Interactions , Models, Molecular , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Animals , Betacoronavirus/classification , Eutheria/virology , HIV-1/genetics , Humans , Metagenome , Pandemics , Protein Structure, Tertiary , Sequence Alignment , Sequence Analysis, Protein , Snakes/virology
4.
SLAS Discov ; : 2472555220942123, 2020 Jul 13.
Article in English | MEDLINE | ID: covidwho-654127

ABSTRACT

COVID-19 respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global health issue since it emerged in December 2019. While great global efforts are underway to develop vaccines and to discover or repurpose therapeutic agents for this disease, as of this writing only the nucleoside drug remdesivir has been approved under Emergency Use Authorization to treat COVID-19. The RNA-dependent RNA polymerase (RdRP), a viral enzyme for viral RNA replication in host cells, is one of the most intriguing and promising drug targets for SARS-CoV-2 drug development. Because RdRP is a viral enzyme with no host cell homologs, selective SARS-CoV-2 RdRP inhibitors can be developed that have improved potency and fewer off-target effects against human host proteins and thus are safer and more effective therapeutics for treating COVID-19. This review focuses on biochemical enzyme and cell-based assays for RdRPs that could be used in high-throughput screening to discover new and repurposed drugs against SARS-CoV-2.

5.
Non-conventional | WHO COVID | ID: covidwho-636676

ABSTRACT

COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2 Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2 The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections

6.
Hypertension ; 76(2): 478-487, 2020 08.
Article in English | MEDLINE | ID: covidwho-610717

ABSTRACT

We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-[1-8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1-8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1-10] (angiotensin [1-10]), the precursor of Ang-[1-8]. Ang-[1-8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1-8]-induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.


Subject(s)
Betacoronavirus , Blood Pressure/physiology , Coronavirus Infections/complications , Hypertension/physiopathology , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/complications , Renin-Angiotensin System/physiology , Animals , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Female , Genotype , Heart Rate/physiology , Hypertension/complications , Hypertension/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , Sex Factors
8.
J Affect Disord ; 269: 201-202, 2020 May 15.
Article in English | MEDLINE | ID: covidwho-115549
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