biomolecules Review COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies Renuka Raman 1,† , Krishna J. Patel 2,† and Kishu Ranjan 3,* 1 Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA; [email protected] 2 Mount Sinai Innovation Partners, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] 3 School of Medicine, Yale University, New Haven, CT 06519, USA * Correspondence: [email protected]; Tel.: +1-203-785-3588 † Authors contributed equally to this work. Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions. Citation: Raman, R.; Patel, K.J.; Keywords: SARS-CoV-2; COVID-19; variants; vaccines; immune dysregulated; comorbidities; anti- Ranjan, K. COVID-19: Unmasking body; spike protein; variants of concern (VOC); biomolecules; coronavirus Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies. Biomolecules 2021, 11, 993. https:// doi.org/10.3390/biom11070993 1. Introduction The catastrophic spread of coronavirus disease 2019 (COVID-19) has already claimed Received: 1 June 2021 millions of lives across the globe and has been declared a public health emergency of Accepted: 29 June 2021 Published: 6 July 2021 international concern by the World Health Organization (WHO) [1] (Figure1). So far, there are seven different types of coronaviruses documented. Among these, four common Publisher’s Note: MDPI stays neutral human coronaviruses—229E, NL63, OC43 and HKU1—cause mild infections [2]. However, with regard to jurisdictional claims in individuals infected with either of the other three coronaviruses—severe acute respiratory published maps and institutional affil- syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS- iations. CoV) and SARS-CoV-2—develop severe respiratory distress and viral pneumonia and may ultimately succumb to the disease [3–5]. SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, is a newly identified, highly diverse, enveloped single-stranded RNA virus [4–7]. It is noteworthy that the nucleotide sequence of SARS-CoV-2 nearly matches (96% similarity) with a bat coronavirus RaTG13 (GenBank: MN996532.1), suggesting the Copyright: © 2021 by the authors. possibility of bats as the most likely progenitors of SARS-CoV-2 and the source for zoonotic Licensee MDPI, Basel, Switzerland. This article is an open access article spillover to human [5,8]. distributed under the terms and The molecular characterization through an RNA-based metagenomic next-generation conditions of the Creative Commons sequencing (mNGS) analysis revealed that the SARS-CoV-2 genome is 29,881 bp in length Attribution (CC BY) license (https:// (GenBank no. MN908947) and encodes 9860 amino acids [9]. The SARS-CoV-2 genome creativecommons.org/licenses/by/ encodes distinct structural and nonstructural proteins. Genes encoding, spike (S) glycopro- 4.0/). tein, envelope (E) glycoprotein, membrane (M) glycoprotein and nucleocapsid (N) protein Biomolecules 2021, 11, 993. https://doi.org/10.3390/biom11070993 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 31 Biomolecules 2021, 11, 993 2 of 30 coding, spike (S) glycoprotein, envelope (E) glycoprotein, membrane (M) glycoprotein constituteand nucleocapsid the structural (N) components, protein constitute whereas 3-chymotrypsin-likethe structural components, protease, papain-likewhereas protease,3-chymotrypsin-like and RNA-dependent protease, papain-like RNA polymerase, protease, in an additiond RNA-dependent to several accessoryRNA poly- pro- teins,merase, constitute in addition the to nonstructural several accessory framework proteins, ofconstitute SARS-CoV-2 the nonstructural [10] (Figure framework2A). The S glycoproteinof SARS-CoV-2 is composed[10] (Figure of 2A). 1273 The amino S glyc acids,oprotein including is composed the Nof terminal1273 amino signal acids, pep- tideincluding (SP, 1–13 the residuesN terminal), the signal S1 peptide (14–685 (SP, residues) 1–13 residues), and S2 the (686–1273 S1 (14–685 residues) residues) subunits. and Furthermore,S2 (686–1273 theresidues) S1 subunit subunits. contains Furthermore, an N-terminal the S1 subunit domain contains (NTD, 14–305an N-terminal residues) anddomain a receptor (NTD, binding14–305 residues) domain and (RBD, a receptor 319–541 binding residues), domain while (RBD, the 319–541 S2 subunit residues), is com- posedwhile ofthe the S2 fusion subunit peptide is composed (FP, 788–806 of the residues), fusion peptide heptapeptide (FP, 78 repeat8–806 residues), sequence 1hep- (HR1) (912–984tapeptide residues repeat ),sequence HR2 (1163–1213 1 (HR1) residues),(912–984 residues), TM domain HR2 (1213–1237 (1163–1213 residues) residues), and TM cyto- plasmdomain domain (1213–1237 (1237–1273 residues) residues and )[cytoplasm11] (Figure do2mainA). The (1237–1273 S1 and S2 residues) subunits [11] are (Figure critical in assembly2A). The andS1 and surface S2 subunits projection are of critical the S protein,in assembly which and interacts surface withprojection cognate of Angiotensin-the S pro- Convertingtein, whichEnzyme interacts 2 with (ACE2) cognate receptors Angioten expressedsin-Converting on the lower Enzyme respiratory 2 (ACE2) pneumocytes receptors ofexpressed the host [5on,12 the]. The lower S protein respiratory is cleaved pneumocy by hosttes transmembraneof the host [5,12]. Serine The ProteaseS protein 2 (TM-is cleaved by host transmembrane Serine Protease 2 (TMPRSS2), into the S1 subunit and S2 PRSS2), into the S1 subunit and S2 subunit at the furin cleavage site (682–689 residues), to subunit at the furin cleavage site (682–689 residues), to facilitate viral fusion and entry facilitate viral fusion and entry [13,14] (Figure2A). Post intracellular entry, SARS-CoV-2 [13,14] (Figure 2A). Post intracellular entry, SARS-CoV-2 hijacks the host cell machinery hijacks the host cell machinery to rapidly synthesize viral envelope, nucleocapsid, and the to rapidly synthesize viral envelope, nucleocapsid, and the replicase polyproteins to as- replicase polyproteins to assemble and release virus progenies [15,16]. Recent studies have semble and release virus progenies [15,16]. Recent studies have identified several identified several SARS-CoV-2 variants (B.1.1.7, B.1.351, P.1, B.1.617, CAL.20C) carrying SARS-CoV-2 variants (B.1.1.7, B.1.351, P.1, B.1.617, CAL.20C) carrying deleterious muta- deleterioustions in the mutations S protein that in the evade S protein host immune that evade recognition, host immune which recognition, further exacerbate which further the exacerbatepathogenicity the pathogenicityand transmission and of transmission COVID-19 [4,5,8] of COVID-19 (Figure 2B). [4,5 Molecular,8] (Figure characteriza-2B). Molecular characterizationtion of different of SARS-CoV-2 different SARS-CoV-2 variants is variantsimperative is imperativeto determine to determinethe transmission the transmis- rate sionand rate further and identify further target identify sites target to de sitesvelop to effective develop therapies effective for therapies COVID-19. for COVID-19. Figure 1. Timeline of major key events in the progression of the COVID-19 pandemic and vaccine development. Counts Figure 1. Timeline of major key events in the progression of the COVID-19 pandemic and vaccine development. Counts shown here are cumulative confirmed (Conf.) cases and deaths worldwide (https://ourworldindata.org/- Source- Johns shownHopkins here areUniversity confirmed CEES cases COVID-19 and deaths DATA, worldwide Accessed (https://ourworldindata.org/ date: 28th May 2021). CQ, Chloroquine;- Source- Johns HCQ, Hopkins Hydroxychloro- University CEESquine; COVID-19 EUA, emergency DATA, accessed use authorization. date: 28 May 2021). CQ, Chloroquine; HCQ, Hydroxychloroquine; EUA, emergency use authorization. The infection and pathogenicity of SARS-CoV-2 in humans was initially reported in the Thelung infection [3], but further and pathogenicity studies identified of SARS-CoV-2 SARS-CoV-2 in humansinfection wasvulnerability initially reportedto other in theorgans, lung including [3], but further liver, brain, studies kidneys identified and intestine SARS-CoV-2 [13,17–20]. infection Studies vulnerability reported that to otheran organs,average including incubation liver, period brain, of kidneys SARS-CoV-2 and intestine in the [host13,17 –is20 approximately]. Studies reported 4–5 days that