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Emerging Therapeutic Modalities against COVID-19 - PubMed

  • ️Wed Jan 01 2020

Review

Emerging Therapeutic Modalities against COVID-19

Shipra Malik et al. Pharmaceuticals (Basel). 2020.

Abstract

The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials.

Keywords: COVID-19; SARS-CoV-2; antiviral; coronavirus; remdesivir; vaccine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

SARS-CoV-2 virus structure and genome. (A) Structure of SARS-CoV-2 virus including membrane (M), spike (S), envelope (E), and nucleocapsid (N) proteins, and single stranded RNA. The size of the virus is reported to be 100–160 nm. (B) The genomic structure of SARS-CoV-2 depicting open reading frames (ORF1a and 1b) with nonstructural proteins like 3CL protease, RNA dependent RNA polymerase (RdRp), helicase, endoribonuclease, and four structural proteins (S, M, E and N).

Figure 2
Figure 2

Clinical trials for COVID-19 treatment. (A) Distribution of COVID-19 clinical trials. Twelve hundred and sixty-five clinical trials are registered for COVID-19, which can be classified into drugs, biologicals, diagnostic tests, devices (respiratory, oxygen therapy, etc), and others (procedures, dietary supplements, etc). Four hundred and forty-seven drug candidates including repurposed and investigational are currently being tested at different stages of clinical trials for COVID-19 treatment. Furthermore, the efficacy of one hundred and forty-three biologicals including vaccines, convalescent plasma therapy, monoclonal antibodies, and stem cells is also being tested for COVID-19. (B) Graphical representation of major therapies against COVID-19 based on number of clinical trials. Chloroquine/hydroxychloroquine is being evaluated in one hundred and seventeen clinical trials for COVID-19 either alone or in combination with additional antiviral or immunomodulatory agents. Convalescent plasma is another major investigational therapy whose efficacy is now being evaluated in fifty-five clinical trials for COVID-19 treatment.

Figure 2
Figure 2

Clinical trials for COVID-19 treatment. (A) Distribution of COVID-19 clinical trials. Twelve hundred and sixty-five clinical trials are registered for COVID-19, which can be classified into drugs, biologicals, diagnostic tests, devices (respiratory, oxygen therapy, etc), and others (procedures, dietary supplements, etc). Four hundred and forty-seven drug candidates including repurposed and investigational are currently being tested at different stages of clinical trials for COVID-19 treatment. Furthermore, the efficacy of one hundred and forty-three biologicals including vaccines, convalescent plasma therapy, monoclonal antibodies, and stem cells is also being tested for COVID-19. (B) Graphical representation of major therapies against COVID-19 based on number of clinical trials. Chloroquine/hydroxychloroquine is being evaluated in one hundred and seventeen clinical trials for COVID-19 either alone or in combination with additional antiviral or immunomodulatory agents. Convalescent plasma is another major investigational therapy whose efficacy is now being evaluated in fifty-five clinical trials for COVID-19 treatment.

Figure 3
Figure 3

Graphical abstract depicting the SARS-CoV-2 replication cycle and site of action for widely studied drugs against COVID-19. (1) The virus enters the host cell by recognizing the ACE2 receptor via spike glycoprotein which induces membrane fusion, resulting in (2) release of viral genome in the cytoplasm. (3) The viral RNA undergoes translation to form polyproteins, which are then cleaved by the viral protease enzyme (CLpro) to form nonstructural proteins like RdRp for replication of viral RNA. Positive sense of viral RNA then undergoes translation to form structural proteins (N, S, M, and E) where S, M, and E are processed in ER (6), while N protein is processed in the cytoplasm where it assembles with a viral RNA replicon. All components are then combined inside the ER-golgi intercompartment (ERGIC) (7), from which virions are released inside the vesicles (8) and secreted outside the cell via exocytosis (9). ACE2: Angiotensin Converting Enzyme 2; TMPRSS2: Type 2 Transmembrane Serine Protease; NSPs: Non-structural proteins; RdRp: RNA dependent RNA polymerase; and CLPro: Coronavirus Protease.

Figure 4
Figure 4

Vaccine candidates currently in clinical trials for COVID-19. (i) mRNA 1273 is a mRNA-based vaccine, which encodes the full-length S protein of SARS-CoV-2 virus and is delivered via lipid nanoparticles (LNPs). (ii) ChAdOx1 nCoV-19 is a chimpanzee adenovirus vector, which expresses the S protein of SARS-CoV-2 virus inside the host cells and activates the immune system. (iii) BNT 162 is a mRNA-based vaccine delivered via LNPs with four candidates (BNT162a1, BNT162b1, BNT162b2, BNT162c2), encoding either the S protein or receptor binding domain (RBD) of S1 subunit. (iv) Ad5-nCoV COVID-19 is a replication defective adenovirus 5 vector (Ad5) encoding the full-length S protein of SARS-CoV-2 virus. (v) COVID-19 aAPC are artificial antigen-presenting cells (aAPC) modified using a lentivirus vector to express fragments of SARS-CoV-2 proteins and immunomodulatory genes. (vi) INO 4800 is a plasmid DNA encoding SARS-CoV-2 proteins and delivered via electroporation using the smart device Cellectra® developed by Inovio. (vii) Synthetic Minigene Vaccine or LV-SMENP-DC are genetically modified dendritic cells (DCs) via a lentivirus vector to express SARS-CoV-2 minigenes (SMEN) and immunomodulatory genes, administered via subcutaneous injection. Furthermore, T cells activated using the modified dendritic cells are also administered via intravenous infusion.

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