A Palmitic Acid-Conjugated, Peptide-Based pan-CoV Fusion Inhibitor Potently Inhibits Infection of SARS-CoV-2 Omicron and Other Variants of Concern

Abstract

Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However, only palmitic acid (C16)-based lipopeptide drugs have been tested clinically, suggesting that the development of C16-based lipopeptide drugs is feasible. Here, we designed and synthesized a C16-modified pan-CoV fusion inhibitor, EK1-C16, and found that it potently inhibited infection by SARS-CoV-2 and its variants of concern (VOCs), including Omicron, and other human CoVs and bat SARS-related CoVs (SARSr-CoVs). These results suggest that EK1-C16 could be further developed for clinical use to prevent and treat infection by the currently circulating MERS-CoV, SARS-CoV-2 and its VOCs, as well as any future emerging or re-emerging coronaviruses.

SARS-CoV-2 fusion-inhibitory lipopeptides maintain high potency against divergent variants of concern including Omicron

“…Compared to the S1 subunit, the fusogenic S2 subunit of SARS-CoV-2 is more conserved during the virus evolution; however, three mutations (Q954H, N969K, and L981F) also exist in the HR1 site of Omicron. It was reported that none of these HR1 mutations affected the interaction between the fusion inhibitor EK1 and an HR1-derived target mimic peptide and the antiviral activity of EK1-based lipopeptides [ 38 , 39 ], which were consistent with our results presented here. Given that IPB02V3 and IPB24 target the different sites and possess a more active inhibitory activity than the EK1-based inhibitors [ 12 , 13 ], they offer ideal candidates for the development of clinically applicable antivirals against the Omicron variant.…”

Potency of Fusion-Inhibitory Lipopeptides against SARS-CoV-2 Variants of Concern

“…The efficacy of SARS-CoV-2-inhibitory peptides at blocking viral transmission ( 7 , 19 , 20 ), taken together with our published data for other viruses ( 21 – 26 ), suggests that an effective antiviral effect can be achieved via administration of antiviral peptides. The potency of these lipopeptides for neutralization of SARS-CoV-2 VOCs is substantial and consistently observed across the VOCs.…”

Pan‐coronavirus fusion inhibitors to combat COVID‐19 and other emerging coronavirus infectious diseases

“…Both HR1 and HR2 regions are relatively conserved in the S protein of HCoVs. 22 , 23 Particularly, amino acid residues at key sites, that is, e and g positions in HR1 helical wheels and a and d positions in HR2 helical wheels, which are directly involved in HR1−HR2 interaction, are the most conserved (Figure 1A , B ). Therefore, HR1 and HR2 domains have served as vital targets for the development of broad‐spectrum HCoV fusion inhibitors.…”

“… 39 However, while no cholesterol‐conjugated peptide or protein drugs have been approved for clinical use so far, a palmitic acid‐conjugated peptide, as an HIV vaccine, has been reported in phase II clinical trials, suggesting that the palmitic acid‐conjugated peptide is safe for use in humans. 23 , 40 Therefore, we have also designed and synthesized a palmitic acid (C16)‐conjugated EK1 peptide, EK1‐C16, and demonstrated that this lipopeptide is also very effective against infection of SARS‐CoV‐2 and its VOCs, including Omicron, as well as other HCoVs. 23 Overall, these EK1‐based lipopeptides are outstanding candidates for clinical development.…”

“… 23 , 40 Therefore, we have also designed and synthesized a palmitic acid (C16)‐conjugated EK1 peptide, EK1‐C16, and demonstrated that this lipopeptide is also very effective against infection of SARS‐CoV‐2 and its VOCs, including Omicron, as well as other HCoVs. 23 Overall, these EK1‐based lipopeptides are outstanding candidates for clinical development.…”