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Review
. 2020;63(1-6):2-9.
doi: 10.1159/000512141. Epub 2020 Oct 23.

Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies

Joseph T Ortega  1 , Jose L Zambrano  2 , Beata Jastrzebska  1 , Ferdinando Liprandi  2 , Hector R Rangel  3 , Flor H Pujol  4
Affiliations
Review

Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies

Joseph T Ortega et al. Intervirology. 2020.

Abstract

Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease CO-VID-19 has strongly encouraged the search for antiviral compounds. Most of the evaluated drugs against SARS-CoV-2 derive from drug repurposing of Food and Drug Administration-approved molecules. These drugs have as target three major processes: (1) early stages of virus-cell interaction, (2) viral proteases, and (3) the viral RNA-dependent RNA polymerase.

Summary: This review focused on the basic principles of virology and pharmacology to understand the importance of early stages of virus-cell interaction as therapeutic targets and other main processes vital for SARS-CoV-2 replication. Furthermore, we focused on describing the main targets associated with SARS-CoV-2 antiviral therapy and the rationale of drug combinations for efficiently suppressing viral replication. Key Messages: We hypothesized that blocking of both entry mechanisms could allow a more effective antiviral effect compared to the partial results obtained with chloroquine or its derivatives alone. This approach, already used to achieve an antiviral effect higher than that offered by every single drug administered separately, has been successfully applied in several viral infections such as HIV and HCV. This review will contribute to expanding the perception of the possible therapeutic targets in SARS-CoV-2 infection and highlight the benefits of using combination therapies.

Keywords: Combination; Coronavirus; Entry; Protease; SARS-CoV-2; Treatment; Virus-host interactions.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
SARS-CoV-2 replication. The viral cycle begins with the interaction between the viral spike and the cellular receptor. Several membrane proteins have been proposed as possible receptors for SARS-CoV-2; however, ACE2 is likely to be the most important one [10]. After the viral spike has interacted with the receptor, the virus gains entry into the host cytosol by two mechanisms: (1) by late endocytosis, releasing the viral RNA after the fusion with the lysosome (this entry is blocked by HCQ), or (2) by early endocytosis by fusion of the viral and host membrane without the participation of the lysosome. In these early stages, the priming processing by cellular proteases is the key for the exposure of the viral fusion motive. TMPRSS2 could act in both early and late endosome entry processes and could be inhibited by benzoic acid derivatives such as nafamostat, camostat, and bromhexine [18, 21]. Furthermore, other proteases such as cathepsin B could mediate the entry in the late lysosomal pathway, while only TMPRSS2 has been related to the early entry endosome [11, 13, 15, 18]. After fusion has occurred, the viral RNA is released into the cytoplasm and open reading frame 1 (ORF1) is translated to produce the RdRp. Subgenomic mRNAs are produced by discontinuous transcription, a process characteristic of this RdRp, which favors recombination. Compounds such as remdesivir, favipiravir, and sofosbuvir block this enzyme [39, 40, 41, 45]. The subgenomic mRNAs are then translated into protein. The genome has eight ORFs. The gene segments that encode nonstructural polyproteins are processed first and translated into ORF1a and ORF1b producing pp1a and pp1ab proteins, respectively. Protein pp1a and pp1ab are cleaved by the viral proteases (3CLpro and PLpro). The main protease is also the target of protease inhibitors such as lopinavir/ritonavir [7]. The structural proteins − spike, envelope, and membrane proteins − enter into the endoplasmic reticulum/Golgi complexes. Then, the nucleoprotein combines with the (+) strand genomic RNA (nucleoprotein complex) and merges with the other structural proteins in the endoplasmic reticulum-Golgi apparatus compartment [64]. Finally, the virion is excreted to the extracellular region through the exosomal pathway [64]. HCQ, hydroxychloroquine; RdRp, RNA-dependent RNA polymerase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2; ORF, open reading frame.
Fig. 2
Fig. 2
Clinical trials using a combination of drugs targeting early replication steps or viral enzymes. An exhaustive revision of the ongoing clinical trials related to SARS-CoV-2 was performed using the database of the National Institutes of Health (NIH) of the United States. The data were accessed from the NIH webserver ClinicalTrials.gov. The search terms were “COVID” or “SARS-CoV-2,” resulting in 3,009 trials. Then, the search parameter drug was applied as a further term, retrieving 1,616 clinical trials. In each search, the trials included those not yet recruiting, recruiting, active, or completed. A visual inspection of each of the 1,616 trials was conducted and only 1,265 included drugs as the main intervention. Moreover, the drug combination trials were also reviewed, and only 113 included a combination of pharmacological therapy for the treatment of COVID-19 patients. The database search was conducted on August 14, 2020. COVID-19, coronavirus disease 2019; HCQ, hydroxychloroquine; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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