key: cord-0743179-bt01f51e
authors: Chen, Zinuo; Du, Ruikun; Galvan Achi, Jazmin M.; Rong, Lijun; Cui, Qinghua
title: SARS-CoV-2 cell entry and targeted antiviral development
date: 2021-05-13
journal: Acta Pharm Sin B
DOI: 10.1016/j.apsb.2021.05.007
sha: 25f14943a8fde34036b286a614ae5a145f0d9c0a
doc_id: 743179
cord_uid: bt01f51e

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19), which threatens human health and public safety. In the urgent campaign to develop anti-SARS-CoV-2 therapies, the initial entry step is one of the most appealing targets. In this review, we summarize the current understanding of SARS-CoV-2 cell entry, and the development of targeted antiviral strategies. Moreover, we speculate upon future directions toward next-generation of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.

respiratory tract is extremely low and limited in the epithelium 25, [28] [29] [30] , however, it's well studied that SARS-CoV-2 preferentially infects cells of the respiratory tract 31 , and SARS-CoV-2 can successfully infect human H522 lung adenocarcinoma cells despite complete absence of ACE2 32 . The existence of alternative host receptors for SARS-CoV-2 entry was therefore speculated. Interestingly, Wang et al. 33 recently identified the tyrosine-protein kinase receptor UFO (AXL) as a candidate receptor that promoting SARS-CoV-2 infection of the human respiratory system. Based on their study, the NTD rather than RBD of SARS-CoV-2 S is responsible for AXL recognition, highlighting the importance of NTD In addition, several other host factors including neuropilin-1, high-density lipoprotein (HDL)-scavenger receptor B type 1 (SR-B1), and cellular heparan sulfate have been reported as co-receptors that may facilitate ACE2-dependent SARS-CoV-2 entry 19, 35, 36 . Moreover, a recent genome-wide CRISPR screening discovered additional proviral host factors for SARS-CoV-2 infection, such as TMEM106B, PIK3C3, and so on 37 .

In addition to receptor binding, host protease activators for SARS-CoV-2 entry have also been examined.

Similar to SARS-CoV, cell surface serine protease transmembrane protease serine 2 (TMPRSS2) and endosomal protease cathepsin L are both important for SARS-CoV-2 entry 16, 17 . In brief, TMPRSS2 cleavage can trigger SARS-CoV-2 S mediated fusion at plasma membrane ( Fig. 2A) , while in TMPRSS2 negative cells, the fusion process can be triggered by cathepsin L in endosomes after clathrin-dependent endocytosis ( Fig. 2B) 38 .

Of particularly note, compared to SARS-CoV, the SARS-CoV-2 S protein displays a multibasic sequence at the S1/S2 junction, which can be recognized by furin or related proprotein convertases [39] [40] [41] .

Considering the furin-like proteases are commonly found in the secretory pathway of most cell lines, the SARS-CoV-2 S protein can be primed during the S maturation process (Fig. 2) 42, 43 . As a result, SARS-CoV-2 virions harbor cleaved S proteins, in contrast to SARS-CoV incorporating S proteins largely uncleaved 10, 16, 17 . In avian influenza viruses, furin-like cleavage site in the surface glycoprotein is a hallmark of high pathogenesis 44 . It seems that this is not the case of SARS-CoV-2, although furin cleavage of S can promote SARS-CoV-2 infection and cell-cell fusion, its role is not essential 10, 45 . On the other hand, due to the near-ubiquitous distribution of furin-like proteases, the additional polybasic cleavage site could putatively expand the tropism of SARS-CoV-2 and/or enhance its transmissibility compared with SARS-CoV 10,46 .

J o u r n a l P r e -p r o o f

As the earliest response, "repurposing" of existing drugs to treat the emerging SARS-CoV-2 infection was proposed. Interestingly, chloroquine and arbidol among these repurposed drugs were confirmed to act by blocking SARS-CoV-2 entry [47] [48] [49] [50] . However, the clinical effect of both chloroquine and arbidol is not satisfactory [51] [52] [53] [54] [55] . Later as our knowledge on the emerging SARS-CoV-2 accumulates, developments of novel drugs specifically targeting SARS-CoV-2 entry followed closely.

Antibody-based therapy can be effective during outbreak of an emerging virus disease. For example, neutralizing antibodies mAb114 and REGN-EB3 have proved their potential therapeutic uses for the treatment of Ebola virus infections [56] [57] [58] .

Considering the close relativity between SARS-CoV-2 and SARS-CoV, primary studies were focused on searching for cross-protective ones from SARS-CoV neutralizing antibodies 22, 59 . However, limited antibody cross-reactivity was observed and SARS-CoV-specific monoclonal antibodies (mAbs) seldom recognize SARS-CoV-2, and only a few mAbs such as CR3022 and S309 bind potently with SARS-CoV- S protein is the primary antigenic target of neutralizing antibodies. Collectively, most of the aforementioned cross-reactive SARS-CoV mAbs and SARS-CoV-2 specific mAbs bind to the RBD of S, preventing its binding to ACE2 receptor. Interestingly, some of them were also defined to recognize the NTD of S, emphasizing the importance of the NTD as a promising target for therapeutic mAbs against COVID-19 68, 69 . Moreover, the NTD-targeting mAbs may be useful to combine with RBD-targeting ones in therapeutic cocktails 69 .

Of particular interest, a series of single-domain antibodies (sdAbs) with potent SARS-CoV-2 neutralizing activities have been reported [81] [82] [83] [84] [85] [86] . SdAbs are small, compact, and thermostable immunoglobulin elements capable of binding target epitopes with subnanomolar affinities 87 . The advances of phage-or yeast-display sdAb libraries greatly facilitated the discovery of SARS-CoV-2neutralizing sdAbs. Notablely, Wu et al. 86 found two sdAbs, n3088 and n3130, which can neutralize SARS-CoV-2 by targeting a "cryptic" epitope located in the spike trimeric interface. Although a previously described mAb CR3022 also recognizes this epitope, it cannot neutralize SARS-CoV-2, J o u r n a l P r e -p r o o f suggesting the advantage of small-size sdAbs to target cryptic eptiopes 86 . Moreover, the high prophylactic and therapeutic efficacy of a bivalent sdAb, VH-Fc ab8, was validated using a hamster model of SARS-CoV-2 infection, with a dose as low as 2 mg/kg 88 . A novel COVID-19 therapy can be therefore anticipated once a SARS-CoV-2 sdAb successfully makes it through preclinical and clinical testing regimens.

The essential role of S-ACE2 interaction during initiation of SARS-CoV-2 entry raised a therapeutic consideration to use soluble ACE2 to inactivate SARS-CoV-2 [89] [90] [91] . Moreover, Guo et al. 92 engineered a trimeric ACE2 exhibiting enhanced binding affinity with S trimers, and the antiviral activity was increased significantly. However, soluble ACE2 shows a short half-life in vivo and no active transport mechanism from the circulation into the alveolar spaces of the lung 89 . To overcome these limitations, further engineering was conducted by fusing ACE2 to the Fc region of the human immunoglobulin IgG1, in order to increase its plasma stability 93, 94 . Alternatively, the N-terminal helix of ACE2 which contains most of the contacting residues at the binding site was mimicked, and the designed peptides exhibit high anti-SARS-CoV-2 activity in vitro [95] [96] [97] . Vice versa, a SARS-CoV-2 RBD-derived hexapeptide YKYRYL has also been proposed to possess inhibitory effect against virus entry by interfering with RBD-ACE2 interaction 98 . 

The development of small molecule entry inhibitors of SARS-CoV-2 fall behind. Besides the aforementioned chloroquine and arbidol, several small molecule inhibitors targeting host proteases have been explored to inhibit SARS-CoV-2 entry, including TMPRSS2 inhibitors camostat mesylate 16 , nafamostat mesylate 106 , and bromhexine hydrochloride 107 , cathepsin L inhibitors E-64d 16,108 , K11777 109 , and SID26681509 110 , and furin inhibitor naphthofluorescein 111 . In general, targeting cellular factors may result in substantial advantages such as a broader range of therapies and reduced chances of developing drug resistance, however, the translational potential of these host protease inhibitors might be limited. For example, the TMPRSS2 can at least partially compensate the furin deficiency, while TMPRSS2 and cathepsin L can compensate the function of each other during SARS-CoV-2 entry, therefore the inhibitory effect of one single inhibitor is typically cell-type dependent and become less potent in vivo.

Although a composition comprising of all classes of protease inhibitors can achieve considerable therapeutic efficacy, increased toxicity should be accompanied. (Table 1 16, 47, 50, [106] [107] [108] [109] [110] [111] 118, 119 ).

Insert Table 1 4

Although it still may require several months to achieve community protection by large-scale vaccination globally, the scientific community better change their mind in advance. Since most drugs developed for emergency use are suboptimal, the following important issues require more attention during development of more valuable SARS-CoV-2 entry inhibitors in the soon-coming post-pandemic era.

Currently, almost all reported SARS-CoV-2 neutralizing mAbs are directed at S1 subunit of S protein 61-70 . However, the high plasticity of S1 makes it easy for the virus to escape immune pressure, and SARS-CoV-2 variants have already emerged, including an early D614G variant and the most recent SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa 8, 120, 121 . These variants are of concern because of their purported ease of transmission and higher virulence. Moreover, due to extensive mutations in the spike protein of these variants, their resistance to antibody neutralizing significantly J o u r n a l P r e -p r o o f increased [122] [123] [124] . As more escape variants might emerge and circulate around the world, the mAbs elicited by the original SARS-CoV-2 strain may totally lose their neutralizing abilities eventually.

The least variable S2 subunit of S is an attractive target for a broad-spectrum neutralizing mAb.

Although most currently identified antibodies induced by natural S2 unit were found to have no neutralizing activities 125 , more efforts should be engaged to search for potent S2-targeted neutralizing mAbs, either from convalescent COVID-19 patients or screen of sdAb libraries. Alternatively, various immune-focusing strategies can be used to prepare S2-based immunogens and elicit antibodies targeting potent neutralizing epitopes that are of low immunogenicity or cryptic within natural S proteins 126 . For example, the epitopes in S1 subunits can either be shielded by hyperglycosylation or removed, so that enhanced antibody response specifically directing to the S2 domain can be anticipated (Fig. 3A and B) [127] [128] [129] [130] . Fig. 3 

Compared to peptides and protein chimeras, small molecules are still the preferred modality for a drug, mainly due to their improved pharmacokinetics, stability, and dosage logistics 131 . However, according to our experience to discover potent entry inhibitors using high-throughput screening approaches against diverse emerging and re-emerging viruses, including Ebola virus, Marburg virus, high-pathogenic influenza H5N1/H7N3 viruses, Lassa virus, as well as SARS-CoV and SARS-CoV-2, the hit rate for SARS-CoV/SARS-CoV-2 entry inhibitors is extremely low [132] [133] [134] . In fact, we have screened a 10,000 small molecule library (Chemdiv, USA) and a 2579 natural product library (MCE, USA) against pseudotyped virus entry of both SARS-CoV and SARS-CoV-2, no specific hit was identified. Although multiple factors are to blame for those negative data, we speculate that there are relatively less druggable pocket in SARS-CoV-2 S that a putative inhibitor can reach and occupy.

Previously, Kalathiya et al. 135 proposed a large cavity formed by the three monomers from S homotrimer, providing a potential target that might assist in future drug discovery programs (Fig. 3C ). By exploring more potential druggable pocket in SARS-CoV-2 S followed by rational design or virtual screen, specific entry inhibitors can be anticipated.

COVID-19 is the third coronavirus-related pandemic in the twenty-first century and has changed the world like never before 136 tail; S1/S2, cleavage site at S1/S2 boundary; S2', a second cleavage site within S2. Alternatively, the virions enter cells via clathrin-dependent endocytosis, and the fusion process can be primed by endosomal cathepsin L (B). Notably, due to the polybasic insertion at S1/S2 boundary of SARS-CoV-2 S, cleavage of S1/S2 can be processed by furin during release of progeny virions through secretory pathways. Immunofocusing strategies to induce S2 specific antibody response by using S immonogens with S1 subunit hyperglycosylated (A) or removed (B). (C) A putative druggable cavity formed by the three monomers from S homotrimer. Small molecule inhibitors targeting to these potent druggable pockets within SARS-CoV-2 S can be anticipated by rational design. The three S monomers were colored by red, blue, and cyan, respectively. J o u r n a l P r e -p r o o f 

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The authors declare no conflicts of interest.