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Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19.

ABSTRACT: An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCov) in vitro. In the United States, one case of COVID-19 was successfully treated with compassionate use of remdesivir in January of 2020. In addition, a clinically proven protease inhibitor, camostat mesylate, has been demonstrated to inhibit Calu-3 infection with SARS-CoV-2 and prevent SARS-2-spike protein (S protein)-mediated entry into primary human lung cells. Here, we systemically discuss the pharmacological therapeutics targeting RNA-dependent RNA polymerase (RdRp), proteinase and S protein for treatment of SARS-CoV-2 infection. This review should shed light on the fundamental rationale behind inhibition of SARS-CoV-2 enzymes RdRp as new therapeutic approaches for management of patients with COVID-19. In addition, we will discuss the viability and challenges in targeting RdRp and proteinase, and application of natural product quinoline and its analog chloroquine for treatment of coronavirus infection. Finally, determining the structural-functional relationships of the S protein of SARS-CoV-2 will provide new insights into inhibition of interactions between S protein and angiotensin-converting enzyme 2 (ACE2) and enable us to develop novel therapeutic approaches for novel coronavirus SARS-CoV-2.

SUBMITTER: Huang J

PROVIDER: S-EPMC7231166 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19.

Huang Jiansheng J Song Wenliang W Huang Hui H Sun Quancai Q

Journal of clinical medicine 20200415 4

An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome ...[more]

PMID: 32326602

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Project description:Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

Dataset Information

Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19.

Publications

Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19.

Similar Datasets

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