The authors provide a foundation for cardiovascular and cardio-oncology physicians on the front line providing care to patients with COVID-19, so that they may better understand the emerging cardiovascular epidemiology and the biological rationale for the clinical trials that are ongoing for the treatment of patients with COVID-19.
Replication of SARS-CoV in host cells
Because of the exceptionally large size of the CoV RNA genome (∼30 kb) and the complexity of CoV-host cell interactions, coupled with the novelty of the SARS-CoV-2 genome, very little is known regarding SARS-CoV-2 replication in cells, let alone how the virus interacts with the host. Given that antiviral strategies are being considered for treatment of patients with COVID-19, here we will review what is generally understood about SARS-CoV replication in mammalian cells, recognizing that this information may change as we learn more about SARS-CoV-2
The Replication Strategy of SARS-CoV
(a) The severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) glycoprotein attaches to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface. On entering the cytoplasm, the viral core particle, which contains the positive (5′ to 3′) strand genomic ribonucleic acid (RNA), is released into the cytoplasm of the cell (b). The positive-strand viral RNA is translated on host ribosomes to generate a large polyprotein (c) that undergoes proteolytic processing to generate multiple viral proteins, including an RNA-dependent RNA polymerase (RdRp). The RNA-dependent RNA polymerase generates a full-length, antisense negative-strand (3′ to 5′) viral RNA strand (d) that serves as template for replicating positive-strand viral genomic RNA, as well as shorter negative-strand RNAs (e) that serve as templates for synthesizing messenger ribonucleic acids (mRNAs) that code for structural proteins of the virus (f), including the S, membrane (M), envelope (E), and nucleocapsid (N) proteins. Translation of viral mRNAs occurs using the host endoplasmic reticulum (ER) (g). Once the viral structural proteins, S, E, and M, are translated and inserted into the ER, they move along the secretory pathway to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (h). The viral proteins become encapsulated and bud into membranes containing viral structural proteins, where mature virions are assembled. (i) Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis. Modified from Turner et al. (43). ORF = open reading frame.
Once the genomic RNA of SARS-CoV is released into the cytoplasm of the host cell, the positive-strand viral RNA is translated on host ribosomes into a large polypeptide termed the replicase, which undergoes proteolytic cleavage to yield proteins that are required from genome replication, including a viral RNA-dependent RNA polymerase. The viral RNA-dependent RNA polymerase generates a full-length, antisense negative-strand viral RNA template, which is used for replicating positive strand viral genomic RNA, as well as shorter subgenomic negative strand RNAs that serve as templates for synthesizing messenger RNAs that code for structural proteins of the virus, including the S, membrane, envelope, and nucleocapsid proteins. Translation of viral messenger RNAs occurs using the host endoplasmic reticulum. Once the viral structural proteins, S, envelope, and membrane, are translated in the endoplasmic reticulum, they move along the secretory pathway to the endoplasmic reticulum-Golgi intermediate compartment. There, the viral proteins become encapsulated and bud into membranes containing viral structural proteins. Following assembly and maturation, virions are transported to the cell surface in vesicles and released by exocytosis
Remdesivir (GS-5734, Gilead Sciences, Inc., Foster City, California) is a nucleoside analog that exhibits broad antiviral activity. Remdesivir is a prodrug that is metabolized to its active form GS-441524, which interferes with the action of viral RNA-dependent RNA polymerase, resulting in a decrease in viral RNA production. It is not known, however, whether remdesivir terminates RNA chains or causes mutations in them. Remdesivir was effective against multiple types of CoVs in cell culture and a mouse model of SARS (45); however, it did not show an effect in patients with Ebola. Remdesivir is currently being tested in several clinical trials for hospitalized patients with COVID-19 and pneumonia . Remdesivir is also 1 of the 4 treatment arms in the multinational SOLIDARITY trial, which is the World Health Organization’s sponsored multinational randomized, open clinical trial to evaluate the safety and comparative efficacy of hydroxychloroquine, remdesivir, the combination of lopinavir and ritonavir, and the combination lopinavir and ritonavir plus interferon-beta . SOLIDARITY will use an adaptive design, which will allow for discontinuation of drugs that lack effectiveness, as well as adding new drugs that appear promising. This type of trial design offers flexibility and efficiency, particularly in the identification of early signals related to either efficacy or toxicity, while maintaining study validity .
Favipiravir (Avigan, Fujifilm Toyama Chemical, Tokyo, Japan) is another nucleoside analog antiviral drug that inhibits viral RNA-dependent RNA polymerase. Like remdesivir, it is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate. Although favipiravir has undergone phase III clinical trials for the treatment of influenza, it is not yet approved by the U.S. Food and Drug Administration (FDA). Japan has granted approval for favipiravir for treating viral strains unresponsive to current antivirals. In preliminary studies, favipiravir was shown to have more potent antiviral activity than lopinavir/ritonavir (47).
Ribavirin (Copegus, Genentech Inc., San Francisco, California) is a prodrug that acts as nucleoside inhibitor. The metabolites of ribavirin resemble adenosine or guanosine nucleosides that then become incorporated into viral RNA and inhibit RNA-dependent replication in RNA viruses. Ribavirin is currently FDA-approved for the treatment of chronic hepatitis C virus infection in combination with peginterferon alfa-2a (Pegasys, Genentech).
COVID-19 and Cardiovascular Disease
The COVID-19 pandemic has presented innumerable challenges to health care organizations and health care providers. Given that the vast majority of patients with cardiovascular disease are at high risk for SARS-CoV-2 infection, the cardiovascular and cardio-oncology communities will play a major role in caring for patients with COVID-19 now and for the foreseeable future. As a community, we have a long tradition of enrolling patients into clinical trials that evaluate therapeutic agents whose mechanisms of action are familiar, which facilitates reaching clinical equipoise when enrolling patients in clinical trials. In the coming months, our communities will be asked to contribute patients to clinical trials where the mechanisms of action of the therapeutic agents are less familiar and the knowledge base required for providing care for COVID-19 is accelerating at a dizzying pace. Here we have tried to provide a foundation for physicians who are on the front line of providing care to patients with COVID-19, so that they can better understand the emerging cardiovascular epidemiology of COVID-19, as well as the biological rationale for the plethora of clinical trials that are either being designed or are currently recruiting patients.
Reference & Source information: https://basictranslational.onlinejacc.org/
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