HKU Discovers Novel Drug Compounds and Associated

Drug Target for Broad-spectrum Antiviral Therapy港大團隊發現全新的廣譜抗病毒藥物及相關靶點

Publication in Nature Communications 10th January 2019

Yuan SF et al, KY Yuen, Department of Microbiology, HKU

Civet, Game mammals

Camels, primates, poultry

Sewage system of

community

Laboratories

Household

Hospitals

Markets

SA

RS

-Co

V(2

00

3)

ME

RS

-Co

V (

20

12

)

Animal handlerGeneral population

Genetic changes

Aggregation

and cross infection

Bat/wild birds (high biodiversity)?

Eb

ola

(2

01

4);

Av

ian

flu

(1

99

7-2

015

)

Selective pressure

Emerging pathogens:

75% from animals

(die out)

The SARS coronavirus was traced to Civets and finally Chinese horseshoe bats prevalent in South China;Most animals infected by other coronaviruses have diarrhea!!!

Guan Y et al, KY Yuen. Science 2003, Lau SKP et al, KY Yuen PNAS 2005

Discovery of >60 novel viruses at HKUDepartment of Microbiology since 2003

1. 2 human viruses: SARS coronavirus & coronavirus HKU1;2. 23 bat viruses: 10 coronaviruses HKU2-10,25 (bat SARS and MERS-like coronaviruses), 3

picornaviruses, 3 tuhokoviruses, 5 bocaparvoviruses, 2 dependoparvoviruses;3. 23 avian viruses: 13 coronaviruses HKU11 to 13, HKU16 to 21 & HKU27 to 30, 3 turdiviruses,

6 picornaviruses, 1 psittacine adenovirus HKU1;4. 3 feline viruses: 1 morbillivirus, 1 picornavirus & 1 astrovirus;5. 3 canine viruses: 1 picodicistrovirus, 1 picornaviruses & 1 norovirus;6. 6 rat viruses: 1 Tailam virus, 1 coronavirus HKU24; 1 bocavirus, 2 rosaviruses & 1 norovirus;

1 hepatitis E virus;7. 1 bovine viruses: 1 partetravirus (hokovirus);8. 5 porcine viruses: 1 coronavirus HKU15, 2 bocaviruses, 1 partetravirus (hokoviruses) & 1

parainfluenzavirus 1;9. 1 ovine partetravirus (hokovirus);10. 1 rabbit coronavirus HKU14;11. 1 dolphin coronavirus HKU22;12. 1 snake paramyxovirus: anaconda paramyxovirus;13. 1 buffalo coronavirus HKU26;14. 3 California sea lion viruses: 2 noroviruses, 1 picobirnavirus;15. 5 camel viruses: 1 coronavirus HKU23, 1 astrovirus, 2 bocaparvoviruses & 1 enterovirus

KY Yuen et al. Lancet, PNAS, J Virol, Plos pathogens, Emeg Infect Dis, J Infect Dis, Virol, J Gen Virol (2003-2018)

Public Health significance:

A. Chinese horseshoe bats as animal origin of SARS(2005)

B. Bat CoV HKU4/5 (2007) discovered 5 years ahead of Middle East MERS epidemic (2012)

C. Bat CoV HKU2 (2007): Mainland outbreaks of fatal swine diarrhea due to HKU2-like CoV (2017)

1997 H5N1

2003 SARS

2013 H7N9

?

Severe pneumonia due to emerging viruses (mortality): avian H5N1(60%),H7N9 (30%); H9N2/H6N1/H10N8/H5N6/H7N4; SARS ( 15%)

Yuen KY et al. Lancet 1998;Chen Y et al. Lancet 2013;To KKW et al. Lancet Infect Dis 2013Peiris J et al KY Yuen, Lancet (2X), 2003

China domestic population migration map 2016 (county)

Needs intensive animal/human surveillance, rapid

diagnostic test, most importantly a broad spectrum

antiviral, & universal (animal & human) vaccines!

Hung IFN et al, KY Yuen. Emerg Infect Dis 2014

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23 to 50% of patients with Middle East Respiratory Syndrome (MERS) also had diarrhea!

Garbati MA et al. Plos One 2016

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SARS patients with diarrhea: colonoscopy biopsy

Perinuclear double membrane vesicles (DMV, 雙膜脂質囊泡 ) for replication of SARS/MERS-CoV (other +SS RNA viruses):

DMV: produced by upregulated phospholipid synthesis （磷脂合成上調） ; protect virus from innate immune detection;

Leung WK et al, KY Yuen. Gastroenterology 2003;Angelini MM et al. Mbio 2013 (nsp3, 4,6)Oudshoorn D et al, mBio 2017

Integrative transcriptomic-lipidomic analysis轉錄組學和脂質組學聯合分析

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Screening bioactive lipid mediators library

脂類化合物庫: 抗病毒活性篩選

AM580

Broad spectrum antiviral effect of AM580

新型的廣譜抗病毒藥物AM580

AM580

Gene expression analysis of lipogenesis pathways

Fatty acid synthesisPathway(13/17genes)

Cholesterol synthesis pathway(10/12 genes)

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脂質合成通路: 基因表達分析

AM580 is predicted to occupy the SRE recognition site of SREBP

SREBP: Sterol regulatory element binding protein 膽固醇調節元件結合蛋白

SRE:膽固醇調節元件

AM580

AM580 佔據了位於膽固醇調節元件結合蛋白上的結合位點

AM580 reduces DMV formation & virus replication

Philips CM100

2950X

11500X

電子顯微鏡顯示AM580顯著減少雙膜脂質囊泡合成

Intranasal AM580 vs Influenza A H7N9 infection in Balb/c mice

Intranasal AM580 6hr post-challenge by intranasal influenza A H7N9 100PFU;Intranasal zanamivir (2mg/kg/D) as +ve control

Serial lung H7N9 viral load reduction &

histopathology improved by AM580 Rx

Intraperitoneal AM580 vs MERS-CoV in DPP4 transgenic mice

Intraperitoneal AM580 12.5mg/kg/D 6hr post challenge by intranasal MERS-CoV 50PFU

Serial lung & brain viral load & lung histopathology

improved by AM580 Rx

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State Key Laboratory of Emerging infectious diseases; Department of Microbiology, HKU: Shuofeng Yuan, Hin Chu, Jasper Fuk-Woo Chan, Zi-Wei Ye, Lei Wen, Bingpeng Yan, Pok-Man Lai, Jingjing Huang, Kah-Meng Tee, Dongdong Chen, Cun Li, Xiaoyu Zhao, Dong Yang, Man Chun Chiu, Cyril Chik-Yan Yip, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Kong-Hung Sze, Jie Zhou, Ivy Hau-Yee Chan, Kelvin Kai-Wang To, Raven Kin-Hang Kok, Richard Yi-Tsun Kao, Johnson Yiu-Nam Lau, Department of Microbiology & Immunology, University of Iowa: Stanley Perlman; Funding from Theme-based Research Scheme (T11-707/15-R) of the Research Grants Council, Health and Medical Research Fund; Michael Seak-Kan Tong, Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, and the Hong Kong Hainan Commercial Association South China Microbiology Research Fund; Patent filed on AM580 analogues as antiviral Rx;

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Q & A

AM580 inhibits SREBP and SRE interaction

SREBP: Sterol regulatory element binding protein膽固醇調節元件結合蛋白

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AM580 抑制膽固醇調節元件與其結合蛋白的相互作用

膽固醇調節元件