Journal
CHEMICAL SCIENCE
Volume 13, Issue 8, Pages 2238-2248Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc04515f
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Funding
- Research Grants Council [R7080-18, T11-709/21N, 2122-7S04]
- Innovation and Technology Fund [ITS/278/20]
- Health and Medical Research Fund
- Food and Health Bureau of the Government of HKSAR [CID-HKU1-11, 19180502]
- Health@InnoHK, Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region
- Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for Department of Health of the Government of HKSAR
- National Program on Key Research Project of China [2020YFA0707500, 2020YFA0707504]
- Sanming Project of Medicine in Shenzhen, China [SZSM201911014]
- High Level-Hospital Program, Health Commission of Guangdong Province, China
- Major Science and Technology Program of Hainan Province [ZDKJ202003]
- University of Hong Kong (URC)
- Shaw Foundation of Hong Kong
- Richard Yu and Carol Yu, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation Limited
- Hong Kong Hainan Commercial Association South China Microbiology Research Fund
- Jessie & George Ho Charitable Foundation
- Perfect Shape Medical Limited, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited
- Betty Hing-Chu Lee, Ping Cham So, and Lo Ying Shek Chi Wai Foundation
- Chan Yin Chuen Memorial Charitable Foundation
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The emergence of SARS-CoV-2 variants impacts vaccine efficacy, highlighting the importance of further developing orally administered anti-SARS-CoV-2 therapies. A cocktail therapy combining colloidal bismuth subcitrate or bismuth subsalicylate with N-acetyl-l-cysteine shows potent preclinical anti-SARS-CoV-2 efficacy, offering a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.
The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs, e.g. colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS), and N-acetyl-l-cysteine (NAC). Oral administration of the cocktail reduced viral loads in the lung and ameliorated virus-induced pneumonia in a hamster infection model. The mechanistic studies showed that NAC prevented the hydrolysis of bismuth drugs at gastric pH via the formation of the stable component [Bi(NAC)(3)], and optimized the pharmacokinetics profile of CBS in vivo. Combination of bismuth drugs with NAC suppressed the replication of a panel of medically important coronaviruses including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E) and SARS-CoV-2 Alpha variant (B.1.1.7) with broad-spectrum inhibitory activities towards key viral cysteine enzymes/proteases including papain-like protease (PLpro), main protease (M-pro), helicase (Hel) and angiotensin-converting enzyme 2 (ACE2). Importantly, our study offered a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.
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