An engineered recombinant protein containing three structural domains in SARS-CoV-2 S2 protein has potential to act as a pan-human coronavirus entry inhibitor or vaccine antigen

Abstract

The threat to global health caused by three highly pathogenic human coronaviruses (HCoV), SARS-CoV-2, MERS-CoV and SARS-CoV, calls for the development of pan-HCoV therapeutics and vaccines. This study reports the design and engineering of a recombinant protein designated HR1LS. It contains three linked molecules, each consisting of three structural domains, including a heptad repeat 1 (HR1), a central helix (CH), and a stem helix (SH) region, in the S2 subunit of SARS-CoV-2 spike (S) protein. It was found that HR1LS protein automatically formed a trimer able to bind with heptad repeat 2 (HR2) region in the SARS-CoV-2 S2 subunit, thus potently inhibiting HCoV fusion and entry into host cells. Furthermore, immunization of mice with HR1LS, when combined with CF501 adjuvant, resulted in the production of neutralizing antibodies against infection of SARS-CoV-2 and its variants, as well as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and MjHKU4r-CoV-1. These results suggest that HR1LS is a promising candidate for further development as a novel HR1-trimer-based pan-HCoV entry inhibitor or vaccine for the treatment and prevention of infection by SARS-CoV-2 and its variants, but also other HCoVs with the potential to cause future emerging and re-emerging infectious coronavirus diseases.

Development of potent pan‐coronavirus fusion inhibitors with a new design strategy

“… 41 , 42 , 43 In contrast, the HR2‐based fusion inhibitors could fully maintain the antiviral efficacy against various SARS‐CoV‐2 variants, even being highly active inhibitors of pan‐sarbecoviruses, as demonstrated by the data described previously and in the current study. 15 , 16 , 44 , 45 , 46 Different from the action mechanism of other classes of antivirals such as paxlovid and molnupiravir, which target the key enzymes (3CL or RdRP) required for viral replication and exert their inhibition after the virus enters the targeting cells, the membrane fusion inhibitors block the early step of infection 38 , 39 , 40 , 41 ; thus, we think that IPB29 has multiple advantages in the treatment and prevention of SARS‐CoV‐2 infection.…”

A Cocktail of Lipid Nanoparticle-mRNA Vaccines Broaden Immune Responses against β-Coronaviruses in a Murine Model

“…Thus, conserved antigenic epitopes have been introduced into pan-sarbeco vaccines in some studies [ 14 , 15 ]. However, the RBD amino acid sequences of MERS-CoV and SARS-CoV/SARS-CoV-2 are significantly different; for this reason, it is difficult to design a shared antigenic sequence to induce sufficient cross-protection against both pathogenic merbecoviruses and sarbecoviruses [ 16 , 17 , 18 , 19 ].…”

Receptor-binding domain-associated serotypes of SARS-CoV-2

“…This suggests the potential classification of pangolin coronavirus into serotype Ia or Ib. Another limitation of this serotype classification system is the lack of considering the antigenicity and immunogenicity of neutralizing epitopes in the conserved regions in S2 subunit of spike protein [ 15 ], which may be important components in some broad-spectrum pan-sarbecovirus or pan-betacoronavirus vaccines. Therefore, more comprehensive and systematic studies are essential for the detailed classification of serotypes within the sarbecovirus family.…”