key: cord-0741389-q6etcwxu authors: Faheem,; Karan Kumar, Banoth; Venkata Gowri Chandra Sekhar, Kondapalli; Kunjiappan, Selvaraj; Jamalis, Joazaizulfazli; Balaña-Fouce, Rafael; Tekwani, Babu L.; Sankaranarayanan, Murugesan title: Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19 date: 2020-09-08 journal: Bioorg Chem DOI: 10.1016/j.bioorg.2020.104269 sha: a628f2caba9b51681336a413af20b54fc4681592 doc_id: 741389 cord_uid: q6etcwxu COVID-19 caused by the novel SARS-CoV-2 has been declared a pandemic by the WHO is causing havoc across the entire world. As of May end, about 6 million people have been affected, and 367 166 have died from COVID-19. Recent studies suggest that the SARS-CoV-2 genome shares about 80 % similarity with the SARS-CoV-1 while their protein RNA dependent RNA polymerase (RdRp) shares 96% sequence similarity. Remdesivir, an RdRp inhibitor, exhibited potent activity against SARS-CoV-2 in vitro. 3-Chymotrypsin like protease (also known as Mpro) and papain-like protease, have emerged as the potential therapeutic targets for drug discovery against coronaviruses owing to their crucial role in viral entry and host-cell invasion. Crystal structures of therapeutically important SARS-CoV-2 target proteins, namely, RdRp, Mpro, endoribonuclease Nsp15/NendoU and receptor binding domain of CoV-2 spike protein has been resolved, which have facilitated the structure-based design and discovery of new inhibitors. Furthermore, studies have indicated that the spike proteins of SARS-CoV-2 use the Angiotensin Converting Enzyme-2 (ACE-2) receptor for its attachment similar to SARS-CoV-1, which is followed by priming of spike protein by Transmembrane protease serine 2 (TMPRSS2) which can be targeted by a proven inhibitor of TMPRSS2, camostat. The current treatment strategy includes repurposing of existing drugs that were found to be effective against other RNA viruses like SARS, MERS, and Ebola. This review presents a critical analysis of druggable targets of SARS CoV-2, new drug discovery, development, and treatment opportunities for COVID-19. against SARS-CoV-2 in vitro. 3-Chymotrypsin like protease (also known as M pro ) and papain-like 23 protease, have emerged as the potential therapeutic targets for drug discovery against 24 coronaviruses owing to their crucial role in viral entry and host-cell invasion. Crystal structures of 25 therapeutically important SARS-CoV-2 target proteins, namely, RdRp, M pro , endoribonuclease 26 Nsp15/NendoU and receptor binding domain of CoV-2 spike protein has been resolved, which 27 have facilitated the structure-based design and discovery of new inhibitors. Furthermore, studies 28 have indicated that the spike proteins of SARS-CoV-2 use the Angiotensin Converting Enzyme-2 29 (ACE-2) receptor for its attachment similar to SARS-CoV-1, which is followed by priming of spike 30 protein by Transmembrane protease serine 2 (TMPRSS2) which can be targeted by a proven 31 inhibitor of TMPRSS2, camostat. The current treatment strategy includes repurposing of existing 32 drugs that were found to be effective against other RNA viruses like SARS, MERS, and Ebola. This 33 review presents a critical analysis of druggable targets of SARS CoV-2, new drug discovery, 34 development, and treatment opportunities for COVID-19. Theoretically, this approach will lead to potent compounds, but the development of these 123 compounds usually takes years, as they undergo the entire drug discovery process. 124 (Fig. 4) . 146 Following the initial findings, Xia et al. and others designed a series of derivatives based on EK-1 147 [28]. EK-1 was covalently linked with cholesterol (designated as EK1C) and palmitic (designated 148 as EK1P) at their C-terminus end with a polyethylene glycol (PEG) spacer (Fig. 4) . Both the 149 peptides exhibited potent fusion inhibition in SARS-CoV-2 mediated cell-cell fusion (IC 50 = 48.1 150 and 69.2 nM for EK1C and EK1P, respectively). Based on the inhibitory potential of EK1C, further derivatives were designed with glycine / serine-based linkers (GSG) and PEG-based spacers. The 152 peptides were designated as EK1C1-EK1C7 (Table 1) . The presence of the linker/spacer and length 153 of the spacer influenced the activity, especially increased the activity of these lipopeptides. The 154 most potent lipopeptide, EK1C4, contained the optimal five residues linker/spacer GSGSG-PGE4. 155 EK1C4 also exhibited potent activity against SARS-CoV-2 pseudovirus infection and live SARS- Orf1ab of viral RNA genome [67] . M pro is known to cleave the replicase polyprotein at 11 specific sites, the recognition sites being Leu-Gln ↓ (Ser, Ala, Gly), to release 12 nsps (nsp4, nsp6-16) that 332 are essential for viral replication as well as viral assembly [10, 67] . Structurally, M pro is a dimer, 333 and each monomer has three domains-domain I, which includes residues 8- 101 Other antivirals that are currently being tested include umifenovir, oseltamivir, 528 darunavir/cobicistat combination (Fig. 19) Hence weak interaction ensues, and the viral entry is prevented [124] . Ivermectin (Fig. 21) is a broad-spectrum anti-parasitic agent [137] . It has also been reported to Following the footsteps of camostat is nafamostat (Fig. 22) Immunomodulators and anti-inflammatory drugs 655 A coordinated effort by the host's immune system is essential for battle against SARS-CoV-2. 656 However, a dysregulated immune response has been reported in patients with COVID-19. 804 COVID-19 infection: the perspectives on immune responses COVID-19 infection: Origin, transmission, 807 and characteristics of human coronaviruses The reproductive number of COVID-19 is higher 810 compared to SARS coronavirus Epidemiology, virology, and clinical features of severe acute respiratory syndrome -812 coronavirus-2 (SARS-CoV-2 Epidemiology, causes, clinical manifestation and diagnosis, prevention and control 816 of coronavirus disease (COVID-19) during the early outbreak period: a scoping review COVID-19 situation reports The epidemiology and pathogenesis of coronavirus disease (COVID-821 19) outbreak Dysosmia and dysgeusia due to the 2019 Novel 823 Coronavirus; a hypothesis that needs further investigation Molecular immune pathogenesis and diagnosis of COVID-826 19 Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by 829 computational methods Coronaviruses-drug discovery and 835 therapeutic options Treatment of SARS with 837 human interferons Inhibition of novel β 839 coronavirus replication by a combination of interferon-α2b and ribavirin Broad-spectrum antivirals for the emerging Middle East respiratory 843 syndrome coronavirus 845 Identification of a Broad-Spectrum Antiviral Small Molecule against Severe Acute Respiratory 846 Syndrome Coronavirus and Ebola, Hendra, and Nipah Viruses by Using a Novel High-Throughput 847 Screening Assay Repurposing of Clinically Developed Drugs for Treatment of Middle East 851 Respiratory Syndrome Coronavirus Infection Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent 901 pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to 902 mediate membrane fusion The first-in-class peptide binder to the 904 SARS-CoV-2 spike protein Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-908 EMC Angiotensin-converting enzyme 2: A functional receptor for 910 SARS coronavirus A pneumonia 914 outbreak associated with a new coronavirus of probable bat origin SARS-CoV-2 Cell Entry 918 Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Counter-regulatory renin-angiotensin system in cardiovascular disease Perinatally administered losartan augments renal ACE2 expression but not cardiac 925 or renal Mas receptor in spontaneously hypertensive rats Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics Angiotensin-converting enzyme 2 (ACE2) as 935 a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target Characterization of spike glycoprotein of SARS-CoV-2 on 939 virus entry and its immune cross-reactivity with SARS-CoV Efficient Activation of the 942 Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease 943 TMPRSS2 Evidence that TMPRSS2 946 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane 947 Fusion and Reduces Viral Control by the Humoral Immune Response Homology Modeling of 950 TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells Inhibitors of 953 cathepsin L prevent severe acute respiratory syndrome coronavirus entry SARS coronavirus, but not human coronavirus 957 NL63, utilizes cathepsin L to infect ACE2-expressing cells Glycopeptide antibiotics potently inhibit cathepsin l in the late endosome/lysosome and 964 block the entry of ebola virus, middle east respiratory syndrome coronavirus (MERS-CoV), and 965 severe acute respiratory syndrome coronavirus (SARS-CoV) Proprotein and prohormone convertases: A family of subtilases 970 generating diverse bioactive polypeptides Characterization of proprotein convertases and their involvement in virus 973 propagation, in: Act. 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