Development of potent pan‐coronavirus fusion inhibitors with a new design strategy
Yuanmei Zhu,
Zhongcai Gao,
Xiaoli Feng,
Lin Cheng,
Nian Liu,
Chao Liu,
Shaowei Han,
Qiaojiang Yang,
Qingcui Zou,
Huihui Chong,
Zheng Zhang,
Minghua Li,
Gengshen Song,
Yuxian He
Affiliations
Yuanmei Zhu
NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen Biology and Center for AIDS Research Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
Zhongcai Gao
Research Institute of Youcare Pharmaceutical Group Co., Ltd Beijing China
Xiaoli Feng
Kunming National High‐level Biosafety Research Center for Non‐Human Primates Center for Biosafety Mega‐Science Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
Lin Cheng
Institute of Hepatology National Clinical Research Center for Infectious Disease Shenzhen Third People's Hospital The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology Shenzhen Guangdong China
Nian Liu
NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen Biology and Center for AIDS Research Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
Chao Liu
Research Institute of Youcare Pharmaceutical Group Co., Ltd Beijing China
Shaowei Han
Research Institute of Youcare Pharmaceutical Group Co., Ltd Beijing China
Qiaojiang Yang
Kunming National High‐level Biosafety Research Center for Non‐Human Primates Center for Biosafety Mega‐Science Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
Qingcui Zou
Kunming National High‐level Biosafety Research Center for Non‐Human Primates Center for Biosafety Mega‐Science Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
Huihui Chong
NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen Biology and Center for AIDS Research Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
Zheng Zhang
Institute of Hepatology National Clinical Research Center for Infectious Disease Shenzhen Third People's Hospital The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology Shenzhen Guangdong China
Minghua Li
Kunming National High‐level Biosafety Research Center for Non‐Human Primates Center for Biosafety Mega‐Science Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
Gengshen Song
Research Institute of Youcare Pharmaceutical Group Co., Ltd Beijing China
Yuxian He
NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen Biology and Center for AIDS Research Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
Abstract Development of potent and broad‐spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion‐inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α‐helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS‐CoV‐2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross‐neutralize the bat‐ and pangolin‐isolated SARS‐CoV‐2‐related CoVs (RatG13, PCoV‐GD, and PCoV‐GX) and other human CoVs (SARS‐CoV, MERS‐CoV, HCoV‐NL63, and HCoV‐229E). Fourth, IPB29 administrated as an inhalation solution (IPB29‐IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS‐CoV‐2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29‐IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS‐CoV‐2 and other coronaviruses.
