Medical Health Clúster A.C.

6 octubre, 2022

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.

Following the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, a novel pathogenic human coronavirus (HCoV) emerged in 2019 that soon spread around the world, resulting in the COVID-19 pandemic1,2. This novel virus was named ‘severe acute respiratory syndrome coronavirus 2’ (SARS-CoV-2) owing to its close sequence homology (~79.6%) with SARS-CoV3,4,5,6. Compared with SARS-CoV and MERS-CoV, SARS-CoV-2 has a much lower case–fatality ratio. However, the high proportions of asymptomatic or mildly symptomatic infections caused by the original strain of SARS-CoV-2 and its ensuing variants have led to higher and more rapid transmissibility of this virus, which has resulted in serious complications for all populations of the world7,8,9,10,11.

Coronaviruses belong to the subfamily Coronavirinae from the family Coronaviridae, and they are genotypically and serologically diversified into four major genera: alphacoronaviruses (alpha-CoVs), betacoronaviruses (beta-CoVs), gammacoronaviruses (gamma-CoVs) and deltacoronaviruses (delta-CoVs)5,7. HCoVs are those coronaviruses that can infect humans. Taxonomically, historically occurring HCoV-229E and HCoV-NL63 are classified as alpha-CoVs, whereas HCoV-HKU1, HCoV-OC43, SARS-CoV, SARS-CoV-2 and MERS-CoV are beta-CoVs. Alpha-CoVs and beta-CoVs mainly infect mammals, whereas gamma-CoVs and delta-CoVs primarily infect birds. Both SARS-CoV-2 and SARS-CoV belong to Sarbecovirus, which is a subgenus of Betacoronavirus. By contrast, MERS-CoV belongs to Merbecovirus, another subgenus of Betacoronavirus. Two other HCoVs of note, HCoV-HKU1 and HCoV-OC43, which can cause common cold-like illnesses, belong to the subgenus Embecovirus of Betacoronavirus7,12,13,14.

HCoVs contain phosphorylated nucleocapsid (N) protein with a single-stranded genomic RNA as a core. The viral core is encapsulated by phospholipid bilayers to form spherical or pleomorphic particles 80–120 nm in size, and is characterized by the presence of the outer surface spike (S) protein7,8. The S protein is composed of two subunits, S1 and S2. S1 contains an important receptor-binding domain (RBD), which is responsible for the recognition of host cell surface receptors that enable virus entry. Both SARS-CoV and SARS-CoV-2 engage angiotensin-converting enzyme 2 (ACE2), which is widely expressed by a variety of human cells, as the primary entry receptor15,16,17. Dipeptidyl peptidase 4 (DPP4; also known as CD26) is the corresponding entry receptor for MERS-CoV17,18. The S2 subunit is mainly responsible for subsequent viral fusion with and entry into the host cell. The junction of S1 and S2 contains a specific furin cleavage site, which is cleaved by host cell furin to facilitate virus entry into cells19. ACE2 engagement by the virus exposes the S2′ cleavage site, and S2 is further cleaved into two parts at this site by transmembrane serine protease 2 (TMPRSS2) at the cell membrane surface, facilitating the process of membrane fusion between the host cell and the virus20. ACE2-bound virus can also be internalized via endocytosis, and in this case, cleavage of the S2′ site is mediated by cathepsins, especially cathepsin L in endosomes21 (Fig. 1a).

Créditos: Comité científico Covid

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