tetano
Editor, Senior Moderator
Cell Discov
. 2022 Sep 8;8(1):88.
doi: 10.1038/s41421-022-00455-6.
A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein
Songyi Xue[SUP] #[/SUP][SUP] 1 [/SUP], Xinling Wang[SUP] #[/SUP][SUP] 2 [/SUP], Lei Wang[SUP] 1 [/SUP], Wei Xu[SUP] 2 [/SUP], Shuai Xia[SUP] 2 [/SUP], Lujia Sun[SUP] 2 [/SUP], Shaohui Wang[SUP] 3 [/SUP], Ning Shen[SUP] 1 [/SUP], Ziqi Yang[SUP] 1 [/SUP], Bo Huang[SUP] 1 [/SUP], Sihao Li[SUP] 1 [/SUP], Chuanhai Cao[SUP] 1 4 [/SUP], Laurent Calcul[SUP] 1 [/SUP], Xingmin Sun[SUP] 3 [/SUP], Lu Lu[SUP] 5 [/SUP], Jianfeng Cai[SUP] 6 [/SUP], Shibo Jiang[SUP] 7 [/SUP]
Affiliations
Abstract
The receptor-binding domain (RBD) in S1 subunit and heptad repeat 1 (HR1) domain in S2 subunit of SARS-CoV-2 spike (S) protein are the targets of neutralizing antibodies (nAbs) and pan-coronavirus (CoV) fusion inhibitory peptides, respectively. However, neither nAb- nor peptide-based drugs can be used orally. In this study, we screened a one-bead-two-compound (OBTC) cyclic γ-AApeptide library against SARS-CoV-2 S protein and identified a hit: S-20 with potent membrane fusion inhibitory activity, but moderate selectivity index (SI). After modification, one derivative, S-20-1, exhibited improved fusion inhibitory activity and SI (>1000). S-20-1 could effectively inhibit infection by pseudotyped and authentic SARS-CoV-2 and pseudotyped variants of concern (VOCs), including B.1.617.2 (Delta) and B.1.1.529 (Omicron), as well as MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. It could also inhibit infection of a pseudotyped SARS-related coronavirus WIV1 (SARSr-CoV-WIV1) from bats. Intranasal application of S-20-1 to mice before or after challenge with HCoV-OC43 or SARS-CoV-2 provided significant protection from infection. Importantly, S-20-1 was highly resistant to proteolytic degradation, had long half-life, and possessed favorable oral bioavailability. Mechanistic studies suggest that S-20-1 binds with high affinity to RBD in S1 and HR1 domain in S2 of SARS-CoV-2 S protein. Thus, with its pan-CoV fusion and entry inhibitory activity by targeting two sites in S protein, desirable half-life, and promising oral bioavailability, S-20-1 is a potential candidate for further development as a novel therapeutic and prophylactic drug against infection by SARS-CoV-2 and its variants, as well as future emerging and reemerging CoVs.
. 2022 Sep 8;8(1):88.
doi: 10.1038/s41421-022-00455-6.
A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein
Songyi Xue[SUP] #[/SUP][SUP] 1 [/SUP], Xinling Wang[SUP] #[/SUP][SUP] 2 [/SUP], Lei Wang[SUP] 1 [/SUP], Wei Xu[SUP] 2 [/SUP], Shuai Xia[SUP] 2 [/SUP], Lujia Sun[SUP] 2 [/SUP], Shaohui Wang[SUP] 3 [/SUP], Ning Shen[SUP] 1 [/SUP], Ziqi Yang[SUP] 1 [/SUP], Bo Huang[SUP] 1 [/SUP], Sihao Li[SUP] 1 [/SUP], Chuanhai Cao[SUP] 1 4 [/SUP], Laurent Calcul[SUP] 1 [/SUP], Xingmin Sun[SUP] 3 [/SUP], Lu Lu[SUP] 5 [/SUP], Jianfeng Cai[SUP] 6 [/SUP], Shibo Jiang[SUP] 7 [/SUP]
Affiliations
- PMID: 36075899
- DOI: 10.1038/s41421-022-00455-6
Abstract
The receptor-binding domain (RBD) in S1 subunit and heptad repeat 1 (HR1) domain in S2 subunit of SARS-CoV-2 spike (S) protein are the targets of neutralizing antibodies (nAbs) and pan-coronavirus (CoV) fusion inhibitory peptides, respectively. However, neither nAb- nor peptide-based drugs can be used orally. In this study, we screened a one-bead-two-compound (OBTC) cyclic γ-AApeptide library against SARS-CoV-2 S protein and identified a hit: S-20 with potent membrane fusion inhibitory activity, but moderate selectivity index (SI). After modification, one derivative, S-20-1, exhibited improved fusion inhibitory activity and SI (>1000). S-20-1 could effectively inhibit infection by pseudotyped and authentic SARS-CoV-2 and pseudotyped variants of concern (VOCs), including B.1.617.2 (Delta) and B.1.1.529 (Omicron), as well as MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. It could also inhibit infection of a pseudotyped SARS-related coronavirus WIV1 (SARSr-CoV-WIV1) from bats. Intranasal application of S-20-1 to mice before or after challenge with HCoV-OC43 or SARS-CoV-2 provided significant protection from infection. Importantly, S-20-1 was highly resistant to proteolytic degradation, had long half-life, and possessed favorable oral bioavailability. Mechanistic studies suggest that S-20-1 binds with high affinity to RBD in S1 and HR1 domain in S2 of SARS-CoV-2 S protein. Thus, with its pan-CoV fusion and entry inhibitory activity by targeting two sites in S protein, desirable half-life, and promising oral bioavailability, S-20-1 is a potential candidate for further development as a novel therapeutic and prophylactic drug against infection by SARS-CoV-2 and its variants, as well as future emerging and reemerging CoVs.