The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.
Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus with a high mutation rate. Importantly, several currently circulating SARS-CoV-2 variants are associated with loss of efficacy for both vaccines and neutralizing antibodies. Methods We analyzed the binding activity of six highly potent antibodies to the spike proteins of SARS-CoV-2 variants, assessed their neutralizing abilities with pseudovirus and authentic SARS-CoV-2 variants and evaluate efficacy of antibody cocktail in Delta SARS-CoV-2-infected hamster models as prophylactic and post-infection treatments. Results The tested RBD-chAbs, except RBD-chAb-25, maintained binding ability to spike proteins from SARS-CoV-2 variants. However, only RBD-chAb-45 and -51 retained neutralizing activities; RBD-chAb-1, -15, -25 and -28 exhibited diminished neutralization for all SARS-CoV-2 variants. Notably, several cocktails of our antibodies showed low IC50 values (3.35–27.06 ng/ml) against the SARS-CoV-2 variant pseudoviruses including United Kingdom variant B.1.1.7 (Alpha), South Africa variant B.1.351 (Beta), Brazil variant P1 (Gamma), California variant B.1.429 (Epsilon), New York variant B.1.526 (Iota), and India variants, B.1.617.1 (Kappa) and B.1.617.2 (Delta). RBD-chAb-45, and -51 showed PRNT50 values 4.93–37.54 ng/ml when used as single treatments or in combination with RBD-chAb-15 or -28, according to plaque assays with authentic Alpha, Gamma and Delta SARS-CoV-2 variants. Furthermore, the antibody cocktail of RBD-chAb-15 and -45 exhibited potent prophylactic and therapeutic effects in Delta SARS-CoV-2 variant-infected hamsters. Conclusions The cocktail of RBD-chAbs exhibited potent neutralizing activities against SARS-CoV-2 variants. These antibody cocktails are highly promising candidate tools for controlling new SARS-CoV-2 variants, including Delta.
Edited by Peter BrzezinskiStructure-based mutagenesis analysis on selected conserved surface basic residues of DENV NS3 helicase was performed using a selectable replicon and recombinant protein. We found a requirement for basic side chains of NS3 residues #225, #268, and #538 to activate viral RNA replication and ensure RNA-stimulated ATPase activity, and a critical role for R560 and R599 residues in maintaining NS3 helicase structure, linked to its biological function and catalytic activity. Three screened NS3 second-site mutations for R225A and R268A/E mutations elevated the functional RNA binding of NS3 helicase and compensated the replication defect of the original NS3 mutant replicons. . The DENV genome encodes a single polyprotein that is processed into three structural proteins (C, prM, E) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) by viral and host proteases. Structural proteins participate in nucleocapsid formation and virion assembly. NS5 RNA-dependent RNA polymerase together with most, if not all, NS proteins are required for viral genome replication [2][3][4].Dengue virus NS3 is a multifunctional protein of 618 residues. In the N-terminal 30% of NS3 together with NS2B mediate viral polyprotein processing [5][6][7]. In the C-terminal 70% of NS3 is a superfamily 2 (SF2) DEAH-box helicase that possesses RNA 5 0 -triphosphatase (RTPase), RNA-stimulated nucleoside triphosphatase (NTPase), 3 0 -tailed dsRNA unwinding, and RNA annealing activities [8][9][10][11][12][13]. DENV NS3 interacts with other NS proteins to exert its biological and biochemical functions. For example, NS3 and NS5 coexist in the heavy membrane fraction of DENV-infected cell lysates that have RNA-dependent RNA polymerase activity [14], and interaction of the NS3 C-terminal domain and NS5 and the NS3 and NS5 N-terminal domain have independently been found to be important for DENV RNA replication [15,16]. The ATPase and RTPase activities of NS3 are modulated by NS5 [17], and the RTPase activity of NS3 is suspected to cooperate with the guanylyl transferase (GTase) and methyltransferase (MTase) activities of NS5 for the 5 0 capping of DENV genome RNA [18][19][20][21]. The NS3 helicase (NS3 h) domain interacts with the cytosolic loop of NS4B transmembrane protein [22]. NS3-NS4B interaction is critical for DENV RNA replication [22,23], and NS4B facilitates dissociation of NS3 helicase from ssRNA [24].Flavivirus NS3 helicase (NS3 h) domains are DEAH/DEAD proteins that have a flattened threelobed structure, corresponding to subdomains 1, 2, and 3. The subdomains 1 and 2 are RecA-like domains containing conserved sequence motifs for NTP binding Abbreviations DENV, Dengue virus; GTase, guanylyl transferase; MTase, methyltransferase; NS, nonstructural; SF2, superfamily 2.
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