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貓冠狀病毒感染過程新發現  有助疫苗與藥物研發

 

    新型冠狀病毒蔓延全球,國外學者也證實病毒已出現變異,繼SARS和MERS造成的嚴重危害,讓人再次見識冠狀病毒的威力與快速變異性。台大分子暨比較病理生物學研究所副教授張惠雯、助理教授張晏禎與中央研究院生化所副研究員徐尚德、特聘研究員邱繼輝,從貓的冠狀病毒感染過程中發現可供未來抗病毒藥物與疫苗之研究技術,成果榮登美國國家科學院院刊(Proceedings of the National Academy of Sciences of the United States of America, PNAS)。

 

 

FIPV胞外同源三聚體棘狀蛋白的結構。左圖為冷凍電顯之高解析度三維蛋白質影像(3.3 Å),其三聚體之單體分別以灰色、黃色與紅色呈現。右圖為FIPV棘狀蛋白之結構模型。

 

    冠狀病毒感染貓會造成高致死性的傳染性腹膜炎(feline infectious peritonitis; FIP),由於診斷困難且缺乏有效之治療及預防方法,發病動物幾乎100%死亡,為伴侶動物急需解決之醫療問題,然而最盛行的第一血清型FIPV不易進行病毒分離,故致病分子機轉、疫苗及抗病毒藥物之開發等相關研究皆受到限制。

 

    為了提供FIP醫療創新思維,並增進對分子層面的認識,研究團隊以哺乳類細胞株表現高度醣化之第一型FIPV棘狀蛋白,結合冷凍電顯與質譜儀,建構該蛋白之立體分子結構與轉譯後修飾醣分子在空間中的分佈與構型。

 

    研究結果顯示,該蛋白之多個子域與其他已知冠狀病毒棘狀蛋白結構大為不同,而且醣分子可能在病毒辨識宿主細胞受器上扮演重要角色,與同源病毒進行比對後,預測出可能與細胞受體結合之結構域,可供未來抗病毒藥物與疫苗之設計參考。研究團隊表示,同樣研究技術在未來可套用於其他冠狀病毒分子結構與功能關係之研究,預期能對社會經濟與國民健康醫療帶來重大貢獻。

研究全文:dio:10.1073/pnas.1908898117

 

左起為張晏禎、張惠雯、徐尚德、台大生物化學所博士生楊子靖、簡瑜君。

Newly found infection process of feline coronaviruses facilitates development of vaccines and medicines

Coronaviruses (CoVs) such as SARS-CoV and MERS-CoV cause severe disasters, including the current COVID-19 global pandemic. Associate Professor Dr. Hui-Wen Chang and Assistant Professor Dr. Yen-Chen Chang of the NTU Graduate Institute of Molecular and Comparative Pathobiology, together with Associate Researcher Dr. Shang-Te Danny Hsu and distinguished Researcher Dr. Kay-Hooi Khoo of the Institute of Biological Chemistry, Academia Sinica, discovered techniques to facilitate developing vaccines and anti-viruses via the infection process of feline coronaviruses (Cryo-EM analysis of a feline coronavirus spike protein reveals a unique structure and camouflaging glycans, Proc. Natl. Acad. Sci. U.S.A., (2020) 117(3), 1438–1446). CoV infection causes highly fatalfeline infectious peritonitis (FIP). Due to the difficulty of diagnosis and the absence of effective cure and prevention, infection isalmost 100% fatal, so it is and emerging medical issue companion animals. However, the prevailing first serum of FIP virus (FIPV) is not easy to isolate, thus studies of the pathogen’s transformations, vaccines, and anti-viruses are restricted.

 

Figure. Cryo-EM structure of FIPV-UU4 S protein. (Left) The 3.3-Å cryo-EM map of FIPV-UU4 S protein is shown in side view with the3 protomers colored in gold, red, and gray. (Right) Figure representative of the atomic model of monomeric FIPV-UU4 S protein.

To provide innovative information about FIP on a molecular scale, the team determined the stereoscopic molecular structure and distribution of glycosyl groups after glycosylation of advanced glycation mammal cell line first type monomeric FIPV-UU4 S protein using cryo-electron microscopy and mass spectrometry. The glycosyl group plays a role in identifying host cell receptors. The result shows that the protein has several discrepancies on the subdomain structure from other known CoV spike proteins. Referencing homologous viruses and then predicting possible structural domains to link to a cell receptor can provide information for producing vaccines and anti-viruses. The team indicates that the same technique has the potential to be applied to studying structures and the functioning of other CoVs, which is expected to benefit society and public health.

The link of the research: doi:10.1073/pnas.1908898117

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