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RESEARCH ARTICLE

Inhibitory Activity of Honeysuckle Extracts against Influenza A Virus In Vitro and In Vivo Mengwei Li1 • Yuxu Wang1 • Jing Jin1 • Jie Dou1 • Qinglong Guo2 • Xue Ke3 • Changlin Zhou1 Min Guo1

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Received: 19 July 2019 / Accepted: 11 September 2020 Ó Wuhan Institute of Virology, CAS 2020

Abstract Honeysuckle has been used in the treatment of influenza virus infection for thousands of years in China. However, its main active components and the functional mechanisms remain to be elucidated. Here, four honeysuckle extracts, including acids extract, flavonoids extract, total extract and acids-flavonoids mixture, were prepared to clarify the main active antiviral components. The cytopathic effect reduction assay showed that all the four extracts inhibited the replication of influenza viruses H1N1, H3N2 and the oseltamivir-resistant mutant strain H1N1-H275Y. The acids-flavonoids mixture had the strongest inhibitory effects in vitro with EC50 values of 3.8, 4.1, and [ 20 lg/mL against H1N1, H3N2 and H1N1H275Y, respectively, showing competitive antiviral activity with oseltamivir and ribavirin. Honeysuckle acids extract also showed the most significant antiviral activity in vivo. Oral administration of the acids extract at a dosage of 600 mg/ kg/d effectively alleviated viral pneumonia, maintained body weight and improved the survival rate to 30% of the mice infected with a lethal dose of H1N1. The results of time-of-drug addition experiment and neuraminidase (NA) inhibition assay showed that honeysuckle extracts had a broad-spectrum inhibitory effect against influenza virus NAs. The flavonoid extract showed the strongest inhibitory effect on the NA of influenza virus H7N9 with an IC50 of 24.7 lg/mL. These results suggested that these extracts might exert their antiviral activity by suppressing the release of influenza viruses. Briefly, our findings demonstrate that acids and flavonoids extracts of honeysuckle are the major antiviral active components, and the acids extract has the potential to be developed into an antiviral agent against influenza virus, especially for oseltamivirresistant viruses. Keywords Honeysuckle extract  Antiviral activity  Influenza A virus (IAV)  Oseltamivir-resistant

Introduction

Mengwei Li and Yuxu Wang contributed equally to this work. & Min Guo [email protected] & Changlin Zhou [email protected] 1

State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China

2

Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China

3

Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

Influenza A virus is a considerable threat to human health and life, and can cause seasonal and widespread epidemics or pandemics with high levels of morbidity and mortality (Taubenberger and Kash 2010; Zhang et al. 2012). The circ