hku discovers novel drug compounds and associated drug … · 2019-01-10 · hku discovers novel...
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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