Key result
Multivalent LCB1 fusion proteins improve SARS-CoV-2 inhibition versus LCB1 despite high-level resistance from XBB variants.
Why the study?
Emerging SARS-CoV-2 variants could substantially compromise the neutralization effectiveness of the computationally designed miniprotein LCB1.
Do multivalent LCB1 fusion proteins inhibit SARS-CoV-2 variants more effectively than monovalent LCB1?
Do multivalent LCB1 fusion proteins inhibit SARS-CoV-2 variants more effectively than monovalent LCB1?
Multivalent LCB1 fusion proteins show improved broad-spectrum antiviral activity against SARS-CoV-2 and related coronaviruses, though recent Omicron subvariants like XBB exhibit high-level resistance.
May warrant further preclinical testing of multivalent inhibitors; leaves open clinical translation against resistant Omicron subvariants.
LCB1 is a computationally designed three-helix miniprotein that precisely targets the spike (S) receptor-binding motif (RBM) of SARS-CoV-2, exhibiting remarkable antiviral efficacy; however, emerging SARS-CoV-2 variants could substantially compromise its neutralization effectiveness. In this study, we constructed two multivalent LCB1 fusion proteins termed LCB1T and LCB1T-Fc, and characterized their potency in inhibiting SARS-CoV-2 pseudovirus and authentic virus in vitro. In the inhibition of various SARS-CoV-2 variants, the two LCB1 fusion proteins exhibited markedly improved inhibitory activities compared to LCB1 as anticipated; however, it was observed that relative to the D614G mutation hosting variant, the variants Delta, Lambda, and Omicron BQ.1.1, XBB, XBB.1.5, and EG.5.1 caused various degrees of resistance to the two fusion proteins' inhibition, with XBB, XBB.1.5, and EG.5.1 variants showing high-level resistance. Moreover, we demonstrated that bat coronavirus RaTG13 and pangolin coronavirus PCoV-GD/PCoV-GX were highly sensitive to two LCB1 fusion proteins, but not LCB1, inhibition. Importantly, our findings revealed a notable decrease in the blocking capacity of the multivalent LCB1 inhibitor on the interaction between the virus's RBD/S and the cell receptor ACE2 when confronted with the XBB variant compared to WT and the Omicron BA.1 variant. In conclusion, our studies provide valuable insights into the antiviral profiling of multivalent LCB1 inhibitors and offer a promising avenue for the development of novel broad-spectrum antiviral therapeutics.
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Jin et al. (2023) studied SARS-CoV-2 infection. Multivalent LCB1 fusion proteins (LCB1T and LCB1T-Fc) vs. LCB1 was evaluated on Inhibition of SARS-CoV-2 pseudovirus and authentic virus in vitro. Multivalent LCB1 fusion proteins exhibited improved inhibitory activities against SARS-CoV-2 variants compared to LCB1, though XBB, XBB.1.5, and EG.5.1 variants showed high-level resistance.
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