However, a recent study showed the diminished role of the Fc region in protecting against lethal SARS-CoV-2 infections in K18-hACE2 transgenic mice . antibodies The spike (S) protein of SARS-CoV-2 is the primary target of neutralizing antibodies (NAbs) (Fig 1A). Therefore, NAbs against SARS-CoV-2 that have either been deployed for therapy or are in advanced stage trials, for the most part, either target the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the spike glycoprotein (Fig 1A and 1B) [1,2]. The S protein exists in different conformations within the host, and their nomenclatures are based on the position of RBD proteinan up or down position (Fig 1B). To this end, based on the epitope recognition and binding mode, RBD-specific NAbs are categorized into 4 major classes (I, II, III, and IV) [3C5]. Class I and II NAbs bind the Pramiracetam angiotensin converting enzyme 2 (ACE2) binding region or receptor-binding motif (RBM) region of the RBD on the spike glycoprotein . The RBM region is responsible for the primary contact with host ACE2 to initiate the entry of the virus . MAbs that block this RBMCACE2 interaction are ACE2 blockers. The class I NAbs bind RBD in up conformation only and block ACE2 binding, whereas class II NAbs block ACE2 binding, and recognize both up and down RBDs Pramiracetam (Fig 1B and 1C). On the other hand, the class Pramiracetam III NAbs block ACE2 binding site, recognize spike protein with both up and down RBD conformations, and can interact with adjacent RBD protomers. The class IV NAbs do not overlap with ACE2 binding site and bind conserved region in RBD (core I region) or RBD in up conformation only (core II region) (Fig 1B and 1C). A complete description of these 4 classes of RBD-dependent mAbs is shown in Fig 1C. Class IV core I region-dependent NAbs have broad neutralizing activity against SARS-CoV-2, its variants, and other related coronaviruses [1C3,7]. Very recently, NAbs targeting new epitopes on the S2 domain (stem helix region) of spike have also been identified that are broadly neutralizing, i.e., neutralize SARS-related and other human coronaviruses (hCoVs) [8C11]. Open in a separate window Fig 1 SARS-CoV-2 spike protein structure, conformation, and targets of RBD-dependent mAbs.(A) SARS-CoV-2 spike protein regions with amino Rabbit Polyclonal to TOP2A (phospho-Ser1106) acid position numbering are shown, which includes S1 domain regions: the SP, NTD, RBD, and RBM and S2 domain regions: FP, HR1 and HR2, TM, and CP. The glycosylation sites are numbered and marked with Y-like structures in blue. (B) Different conformations of spike protein (PDB: 7DF3, 6XKL, 7EB5, and 7KML, left to right). (C) Representation of 4 classes of SARS-CoV-2 RBD dependent mAbs. Antibody variable heavy chain region (sky blue) and light chain variable region (magenta) are marked. Antibody constant regions were removed from the bound Fab for clarity. The RBD is shown in (pale green) color and antibody contacts on RBD are marked in red (PDB ID: left to right, 7CM4 (CT-P59), 7CHF (BD-368-2), 7K90 (C144), and 6R6X (S304 (left) and S309 (right)). RBD class IV core II region targeting mAbs are shown in blue. CP, cytoplasmic tail; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; mAb, monoclonal antibody; NTD, N-terminal domain; PDB, Protein Data Bank; RBD, receptor-binding domain; RBM, receptor-binding motif; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; SP, signal peptide; TM, transmembrane domain. Therapeutic COVID-19 mAbs in the clinic Pramiracetam and in clinical trials Therapeutic mAbs for COVID-19 treatment have been developed in accelerated time and the pace has been unprecedented for any disease. The.