Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 80 million cases and 1.7 million deaths to date while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19.

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COVID-19 Drug Discovery Using Intensive Approaches

International Journal of Molecular Sciences ◽

10.3390/ijms21082839 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2839 ◽

Cited By ~ 13

Author(s):

Ayumu Asai ◽

Masamitsu Konno ◽

Miyuki Ozaki ◽

Chihiro Otsuka ◽

Andrea Vecchione ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Rna Viruses ◽

Drug Repurposing ◽

Global Scale ◽

Therapeutic Agents ◽

Clinical Development ◽

World Health ◽

Antiviral Therapies ◽

The World ◽

Health Organization

Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.

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Tracking the amino acid changes of spike proteins across diverse host species of severe acute respiratory syndrome coronavirus 2

iScience ◽

10.1016/j.isci.2021.103560 ◽

2021 ◽

pp. 103560

Author(s):

Srinivasulu Yerukala Sathipati ◽

Sanjay K. Shukla ◽

Shinn-Ying Ho

Keyword(s):

Amino Acid ◽

Severe Acute Respiratory Syndrome ◽

Host Species ◽

Spike Proteins

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Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry

10.1101/2020.06.15.151779 ◽

2020 ◽

Cited By ~ 13

Author(s):

Seiya Ozono ◽

Yanzhao Zhang ◽

Hirotaka Ode ◽

Toong Seng Tan ◽

Kazuo Imai ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Causative Agent ◽

Cell Entry ◽

Viral Infectivity ◽

Converting Enzyme ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Naturally Occurring ◽

Spike Proteins

AbstractThe causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.

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Anti-HIV drug repurposing against SARS-CoV-2

RSC Advances ◽

10.1039/d0ra01899f ◽

2020 ◽

Vol 10 (27) ◽

pp. 15775-15783 ◽

Cited By ~ 22

Author(s):

Peng Sang ◽

Shu-Hui Tian ◽

Zhao-Hui Meng ◽

Li-Quan Yang

Keyword(s):

Public Health ◽

Severe Acute Respiratory Syndrome ◽

Drug Repurposing ◽

Respiratory Illness ◽

Human Coronavirus ◽

Anti Hiv

A novel severe acute respiratory syndrome human coronavirus (SARS HCoV) was identified from respiratory illness patients (named SARS-CoV-2 by ICTV) in December 2019 and has recently emerged as a serious threat to world public health.

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Insights into the Severe Acute Respiratory Syndrome Coronavirus-2: Transmission, Genome Composition, Replication, Diagnostics and Therapeutics

Current Journal of Applied Science and Technology ◽

10.9734/cjast/2020/v39i2130825 ◽

2020 ◽

pp. 71-91

Author(s):

Rubi Gupta ◽

Ricky Raj Paswan ◽

Richita Saikia ◽

Basanta Kumar Borah

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Vaccine Development ◽

Drug Repurposing ◽

Scientific Basis ◽

World Health ◽

Viral Receptor ◽

Angiotensin Converting Enzyme 2 ◽

Therapeutic Development ◽

Private Sector Organizations ◽

Health Organization

The Severe Acute Respiratory Syndrome Coronavirus-2, originated in Wuhan, China in late 2019 has created a massive pandemic; the disease manifested by the virus was named as COVID-19 by World Health Organization. It has appeared as an unprecedented threat against the global health scenario, as well as the world socio-economic-political structure. The infection of the plausibly animate-origin virus, per se, is not dangerous; but its extremely contagious and infectious nature is the major challenge it has posed. In human, the viral receptor is angiotensin converting enzyme-2, which is present in the cellular membranes of multiple vital organs. The virus has different longevity in different contaminated surfaces which are the principal modes of its transmission. No immunity has so far been reported against the virus; however, immuno-compromised individuals are more vulnerable. For its diagnosis, mainly reverse transcription-based diagnosis is presently being used; however, serological diagnosis is still not a regular practice due to several reasons. Multiple public as well as private sector organizations are working towards vaccine development; research for antiviral drugs and drug-repurposing is also in progress. Several candidate vaccines and drugs are now in various levels of clinical trials. Here, we summarize the scientific basis of the pandemic; its diagnosis, treatment and efforts towards therapeutic development. These efforts will prove useful against future emerging and re-emerging human and non-human epidemics as well as pandemics.

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Emerging SARS-CoV-2 variants of concern and potential intervention approaches

Critical Care ◽

10.1186/s13054-021-03662-x ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Jasmin Khateeb ◽

Yuchong Li ◽

Haibo Zhang

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Clinical Outcome ◽

Therapeutic Strategies ◽

Spike Protein ◽

Host Responses ◽

Structural Protein ◽

Potential Intervention ◽

Viral Virulence ◽

Protein Mutations ◽

Spike Proteins

AbstractThe major variant of concerns (VOCs) have shared mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins, mostly on the S1 unit and resulted in higher transmissibility rate and affect viral virulence and clinical outcome. The spike protein mutations and other non-structural protein mutations in the VOCs may lead to escape approved vaccinations in certain extend. We will discuss these VOC mutations and discuss the need for combination therapeutic strategies targeting viral cycle and immune host responses.

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Drug Repurposing of Lactoferrin Combination in a Nanodrug Delivery System to Combat Severe Acute Respiratory Syndrome Coronavirus-2 Infection

Dr. Sulaiman Al Habib Medical Journal ◽

10.2991/dsahmj.k.210810.001 ◽

2021 ◽

Author(s):

Assem Barakat ◽

Abdullah Mohammed Al-Majid ◽

Gehad Elarag ◽

M. Ali ◽

Ahmed Mostafa ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Delivery System ◽

Drug Repurposing ◽

Nanodrug Delivery

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Ivermectin for COVID-19: A broad-spectrum veterinary endectocide with antiviral activity

10.51128/jfas.2020.a001 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Sharun Khan ◽

Faslu Rahman C K ◽

Jose Bosco ◽

Irshad A ◽

Dhama Kuldeep ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Antiviral Activity ◽

Broad Spectrum ◽

Therapeutic Potential ◽

Natural Infection ◽

Drug Repurposing ◽

Importin Α ◽

Parasitic Activity ◽

Wonder Drug

Severe Acute Respiratory Syndrome coronavirus 2 (SARS CoV 2) is a novel zoonotic coronavirus that has emerged from Wuhan, China. Compared to its predecessors, Severe Acute Respiratory Syndrome CoV (SARS CoV) and Middle East Respiratory Syndrome CoV (MERS CoV), SARS CoV 2 has exhibited efficient human-to-human transmission. In addition to the efficient human-to-human transmission, SARS CoV 2 is also reported to infect other animal species such as cats, tigers, lions, dogs, and minks. The susceptibility of other felines such as cheetah, puma, jaguar, leopard, and lynx are unknown. The reports of SARS CoV 2 natural infection in animals opens up several opportunities to identify suitable animal models for the evaluation of SARS CoV 2 specific vaccines and therapeutics. Ivermectin is a macrocyclic lactone endectocide that has broad-spectrum anti-parasitic activity. The wonder drug ivermectin was also found to possess anti-viral, anti-bacterial, and anti-cancer activity. The antiviral activity exhibited by ivermectin against SARS CoV 2 is believed to be mediated via targeting the importin α/β-mediated nuclear transport and requires further validation. Since the antiviral activity of ivermectin is through a host-directed mechanism, it can reduce the viral load even if administered at a lower dose. Further studies are required to evaluate the efficacy of ivermectin based on in vivo as well as the clinical trials. Being an FDA approved antiparasitic drug, repurposing it for treating COVID-19 patients will be an easy task once it is found to have therapeutic potential.

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