SARS-CoV-2: Repurposed Drugs and Novel Therapeutic Approaches-Insights into Chemical Structure-Biological Activity and Toxicological Screening

Abstract

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic represents the primary public health concern nowadays, and great efforts are made worldwide for efficient management of this crisis. Considerable scientific progress was recorded regarding SARS-CoV-2 infection in terms of genomic structure, diagnostic tools, viral transmission, mechanism of viral infection, symptomatology, clinical impact, and complications, but these data evolve constantly. Up to date, neither an effective vaccine nor SARS-CoV-2 specific antiviral agents have been approved, but significant advances were enlisted in this direction by investigating repurposed approved drugs (ongoing clinical trials) or developing innovative antiviral drugs (preclinical and clinical studies). This review presents a thorough analysis of repurposed drug admitted for compassionate use from a chemical structure-biological activity perspective highlighting the ADME (absorption, distribution, metabolism, and excretion) properties and the toxicophore groups linked to potential adverse effects. A detailed pharmacological description of the novel potential anti-COVID-19 therapeutics was also included. In addition, a comprehensible overview of SARS-CoV-2 infection in terms of general description and structure, mechanism of viral infection, and clinical impact was portrayed.

Keywords: SARS-CoV-2; chloroquine; convalescent plasma; hydroxychloroquine; lopinavir/ritonavir; remdesivir.

Figure 1

The European Region coronavirus disease (COVID-19) cases situation reported on 4 May 2020 according to World Health Organization (WHO) reports (in the graphic are presented only the countries with more than 5000 cases at that date) [8].

Figure 2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structure. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 3

Mechanism of SARS-CoV-2 viral infection: (1) activation of S glycoprotein by transmembrane protease serine 2 (TMPRSS2); (2) activated S glycoprotein binds to the angiotensin-converting enzyme 2 (ACE2) receptor located on human cells surface (target for CQ—chloroquine and HCQ—hydroxychloroquine); (3) internalization and viral membrane fusion; (4) release of the uncoated RNA into the host cell (target for CQ and HCQ); (5) translation into the replicase polyproteins pp1a and pp1ab; (6) formation of replication–transcription complex (RTC) involved in replication and translation of structural proteins and synthesis of subgenomic mRNA, a process that occurs in the cytoplasm of the host cell; (7) assembly of the newly form viral RNA and the structural proteins to form the virion (in the rough endoplasmic reticulum and Golgi apparatus); (8) transport of the virions via vesicles that fuse with the plasmatic membrane; (9) release of the virus in the extracellular space via exocytosis; and (10) spread of the virus and viral infection. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 4

Schematic overview of the steps involved in SARS-CoV-2 infection from the first contact with the virus until the final phase—death or recovery. This image contains Servier Medical Art elements, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 5

Chemical structure of the prodrug Remdesivir (RDV) and its active form GS-441524. Absorption, distribution, metabolism, and excretion (ADME) profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 6

The nsp12-nsp7-nsp8 complex bound to the template-primer RNA and triphosphate form of RDV, Protein Data Base (PDB) ID: 7BV2 (left); RDV covalently bound to U20; hydrogen bonds are depicted as light green dotted lines, amino acid residues in dark green, and nucleotides in orange.

Figure 7

Chemical structure of chloroquine (A) and hydroxychloroquine (B) ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability, covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 8

Chemical structure of Lopinavir; ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 9

Chemical structure of Ritonavir; ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 10

Chemical structure of oseltamivir ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 11

Chemical structure of ribavirin; ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 12

Chemical structure of Umifenovir; ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].

Figure 13

Chemical structure of betulinic acid ADME profile was achieved using the free web tool SwissADME; the red highlighted area represents the suitable physicochemical space for oral bioavailability covering value intervals for the following: LIPO (lipophility): −0.7 < XLOGP3 < +5.0, SIZE: 150 g/mol < MV < 500 g/mol, POLAR (polarity): 20Ų < TPSA < 130Ų, INSOLU (insolubility): 0 < Log S (ESOL) < 6, INSATU (insaturation): 0.25 < Fraction Csp3 < 1, FLEX (flexibility): 0 < Num. rotatable bonds < 9, whereas the overlapped green highlighted area shows the calculated ADME profile for the molecule [63].