食用菌活性成分的抗病毒作用研究進(jìn)展

張相鋒

食用菌活性成分的抗病毒作用研究進(jìn)展

張相鋒

（伊犁師范大學(xué)微生物資源保護(hù)與開發(fā)利用重點(diǎn)實(shí)驗(yàn)室，新疆 伊寧 835000）

食用菌代謝產(chǎn)生的豐富生物活性物質(zhì)，具有抗癌、抗菌、抗病毒、抗氧化和抗炎等作用。人類很多疾病的病原體是病毒?；瘜W(xué)抗病毒藥物的毒副作用及病毒對現(xiàn)有抗病毒藥物的抗藥性，要求我們開發(fā)更多安全性高的天然藥物。通過綜述食用菌中分離出的活性成分對人類免疫缺陷病毒、流感、乙型和丙型肝炎等病毒的作用效果研究進(jìn)展，指出應(yīng)對食用菌進(jìn)行更深入的研究和開發(fā)，以獲得更多天然、安全、有效的抗病毒藥物。

食用菌；抗病毒；人類免疫缺陷病毒；流感病毒；肝炎病毒

食用菌含有豐富的蛋白質(zhì)、人體必需氨基酸、維生素、礦物質(zhì)元素、膳食纖維，以及大量有益于健康的活性物質(zhì)，不含膽固醇，是一種世人公認(rèn)的健康食品。食用菌在代謝過程產(chǎn)生的次生代謝物，如多肽、活性蛋白、萜類、多糖等，具有抗菌、消炎、抗病毒、抗腫瘤和調(diào)節(jié)免疫等效用。因此，食用菌既是營養(yǎng)食品，又是良好的藥用資源。

在人類眾多疾病中，有一部分是由病毒感染導(dǎo)致的，如常見的人類免疫缺陷病毒HIV（又稱艾滋病病毒）、乙型肝炎病毒HBV、流感病毒等，對人類健康造成很大威脅?？共《舅幬锬軞绮《尽⒁种撇《緩?fù)制和傳播的藥物。目前臨床上應(yīng)用的抗病毒藥物多為化學(xué)合成，且有一定的毒副作用。食用菌作為日常生活中食藥功效兼?zhèn)涞拇笮驼婢?，在藥物開發(fā)中具有非常高的安全優(yōu)勢。基于此，科學(xué)家們對食用菌活性代謝物進(jìn)行了大量研究，發(fā)現(xiàn)其中很多成分對病毒有顯著的抗性，在抗病毒方面有很高的應(yīng)用價(jià)值，如凝集素、萜類物質(zhì)、多糖等。以下對食用菌源活性成分在抗病毒方面的研究成果進(jìn)行摘要綜述。

1 對HIV的作用

HIV（Human Immunodeficiency Virus）是一種攻擊人體免疫系統(tǒng)的病毒，它把人體免疫系統(tǒng)中最重要的CD4+T淋巴細(xì)胞作為主要攻擊目標(biāo)，通過大量破壞該細(xì)胞使人體喪失免疫功能，其癥狀又稱為獲得性免疫缺陷綜合癥（Acquired Immune Deficiency Syndrome，AIDS），即艾滋病。由于感染該病毒后死亡率非常高，是嚴(yán)重危害人類健康的病毒之一。HIV的入侵過程有兩個(gè)關(guān)鍵步驟：一是病毒顆粒表面的包膜糖蛋白（Env）通過與免疫細(xì)胞表面的CD4分子、輔助受體互作，實(shí)現(xiàn)病毒與宿主細(xì)胞的融合[1]；二是進(jìn)入宿主細(xì)胞后，病毒利用自身的逆轉(zhuǎn)錄酶（Reverse transcriptase，RT）將RNA轉(zhuǎn)變成DNA整合到宿主和基因組中實(shí)現(xiàn)真正的入侵。在HIV藥物研發(fā)中，主要也以這兩個(gè)環(huán)節(jié)作為切入點(diǎn)。

研究表明，一些食用菌的活性成分表現(xiàn)出較好的抗HIV活性，主要是對逆轉(zhuǎn)錄酶活性的抑制。如一種從大白口蘑（）提取的低分子量漆酶（LAC），顯著抑制HIV-1的RT活性[2]；從猴頭菇（）[3]、靈芝（）[4, 5]、雞腿菇（）[6]、紫丁香蘑（）[7]、香菇（）[4, 8]和杏鮑菇（）[9]中分離到的漆酶同樣具有RT活性；從斑玉蕈（）中提取的Marmorin（一種核糖體抑制蛋白），也具有HIV-1 RT抑制活性[10]；從榆黃蘑（）[11]、大白菇（）[12]、猴頭菇[13]、多脂鱗傘（）[14]、茶褐絲蓋傘（）[15]等食用菌中分離的凝集素具有顯著的HIV-1 RT抑制活性；蛹蟲草（）的血凝素中發(fā)現(xiàn)具有HIV-1 RT抑制活性物質(zhì)[16]；虎乳芝（）提取物也具有抗HIV-1 RT活性[17]；從裂褶菌（）中提取的溶血素[18]，以及來自紫丁香蘑的金屬蛋白酶[19]都表現(xiàn)有抗HIV-1 RT活性；一種新的杏鮑菇多糖肽復(fù)合物及其多肽對HIV-1 RT有抑制作用[20, 21]；從元蘑（）提取的一種新的核糖核酸酶也被證實(shí)有HIV-1 RT抑制活性[22]。

樺褐孔菌（）中的一種水溶性高分子量木質(zhì)素對HIV-1蛋白酶有抑制作用[23]。從姬菇（）中提取的泛素樣蛋白酶和從靈芝中分離出的羊毛脂烷型三萜類化合物顯示出對HIV-1蛋白酶的抑制活性[24, 25]?；⑷橹ゴ继嵛锖退嵛飳IV-1蛋白酶有顯著的抑制活性[17]。香菇菌絲體中的多羧化水溶性木質(zhì)素具有抗HIV活性，它能夠抑制HIV感染的小鼠體內(nèi)類似于人類T4細(xì)胞的HIV抗原表達(dá)過程[26]。

2 對肝炎病毒的作用

肝炎病毒是一類以侵害肝臟引起病變的古老病毒。主要分為：甲型肝炎病毒（HAV）、乙型肝炎病毒（HBV）、丙型肝炎病毒（HCV）、丁型肝炎病毒（HDV）、戊型肝炎病毒（HEV）等。其中甲肝、乙肝和丙肝3種病毒比較常見。甲肝病毒為單正鏈線性RNA病毒，主要通過糞口途徑傳播，易在人群中爆發(fā)，但危害小、易治療、可預(yù)防、可自愈。乙型肝炎病毒為不完全雙鏈DNA病毒，主要通過密切接觸和血液進(jìn)行傳播，是所有肝炎病毒中致病力最強(qiáng)、危害最大、最難治療的，目前主要通過接種疫苗等途徑進(jìn)行預(yù)防。丙型肝炎病毒為+ssRNA病毒，主要通過血液及其相關(guān)制品進(jìn)行傳播，危害性僅次于乙型肝炎病毒。

甲型肝炎病毒雖然易爆發(fā)，但一般可以自愈，所以少有人研究。對于肝炎病毒的預(yù)防和治療的研究主要集中在乙型肝炎病毒和丙型肝炎病毒。一項(xiàng)對乙型肝炎患者使用姬松茸（）提取物12個(gè)月的臨床研究結(jié)果，患者肝功能均恢復(fù)正常[27]。靈芝多糖組分和三萜類化合物對乙肝病毒有一定的抑制作用[28]。從灰樹花（）中提取的D-組分與人干擾素α-2b聯(lián)合使用對乙型肝炎病毒有更好的抑制作用[29]。平菇（）凝集素能夠通過激活TLR6信號通路克服轉(zhuǎn)基因小鼠對HBV的耐受性[30]，其作為乙肝病毒DNA疫苗的佐劑，能增強(qiáng)免疫應(yīng)答[31]。用高效液相色譜技術(shù)從靈芝中分離出的6種有機(jī)酸中，有3種對乙型肝炎病毒抗原分泌具抑制作用[32]。茯苓（）多糖II作為佐劑與乙肝疫苗聯(lián)合使用時(shí)，能增強(qiáng)免疫反應(yīng)[33]。樟芝（）多糖能有效抑制HBV抗原[34]。茶樹菇（）和斑玉蕈水提物可以抑制宿主細(xì)胞中人HBV抗原的表達(dá)[35]。自香菇中分離純化出一種抗病毒蛋白YP46-46，對HBV表面抗原有抑制作用[36]。香菇多糖在體外也具有顯著的HBV抑制活性[37]。豬苓（）多糖單獨(dú)使用或與其他藥物聯(lián)合用于預(yù)防和治療乙型肝炎患者，有非常好的療效[38]。從靈芝中提取的靈芝酸可抑制HepG2215細(xì)胞中HBV的復(fù)制[39]。

香菇菌絲提取物可抑制HCV進(jìn)入細(xì)胞[40]。姬松茸提取物對治療慢性丙型肝炎，顯示出明顯效果[41]。從平菇中純化的LAC可阻止HCV進(jìn)入外周血細(xì)胞和肝癌細(xì)胞[42]。雙孢蘑菇（）水酶提取物在體外對HCV 蛋白酶NS3有抑制作用[43]。網(wǎng)蓋紅褶傘（）中分離的化合物羅丹?。≧hodatin音譯）對HCV有較強(qiáng)的抑制作用[44]。在HCV感染的huh7.5細(xì)胞中，蛹蟲草提取物可降低HCV核心蛋白或NS3蛋白的表達(dá)，從而表現(xiàn)出對HCV的抑制作用[45]。

3 對流感病毒的作用

流感病毒是人類健康的最大威脅之一。全球每年感染流感病毒的病例在6億～12億，重癥病例死亡率為8%～10%。根據(jù)流感病毒核蛋白（NP）和基質(zhì)蛋白（MP）抗原性可分為甲（A）、乙（B）、丙（C）三類，最容易在人群中造成大流行的是甲（A）型流感病毒，這是一種-ssRNA病毒，是目前人類研究的主要對象。

裂蹄木層孔菌（）菌絲提取物作為佐劑可以提高疫苗對變異的H5N1高致病流感病毒交叉感染的保護(hù)作用[46]?？沽鞲胁《灸⒐街械奈?、鋅和鎂等微量元素可能通過刺激宿主的固有免疫反應(yīng)來預(yù)防流感[47]。軟異薄孔菌（）、粗糙擬迷孔菌（）、擬皺皮菌（）、彩絨革蓋菌（）、偏腫栓孔菌（）、苦白蹄（）、樺褶孔菌（）的提取物對人類H3N2和高致病性禽流感H5N1病毒有顯著的抗性[48]。蓋鮑氏針層孔菌（）乙醇提取物中的多酚類物質(zhì)能非競爭性地抑制H1N1、H5N1和H3N2神經(jīng)氨酸酶活性，并減少病毒誘導(dǎo)的細(xì)胞病變（CPE）數(shù)量[49]。香菇菌絲體固體培養(yǎng)提取物通過直接作用于病毒生長和促進(jìn)宿主先天免疫而具有抗流感病毒活性[50]。裂蹄木層孔菌水提取物對甲型和乙型流感病毒有效，包括2009年大流行性H1N1、人H3N2、禽H9N2和奧司他韋耐藥H1N1病毒[51]。Tetiana等研究發(fā)現(xiàn)，被研究的10種食用菌菌絲提取物都能抑制流感病毒H1N1在MDCK細(xì)胞中的繁殖[52]。從相鄰小孔菌（）甲醇提取物中分離出的4種神經(jīng)氨酸酶抑制劑，對流感病毒有特異的抑制性[53]。來自香菇、茯苓（）、生姜、陳皮的混合多糖（MPs）可通過激活體液和細(xì)胞免疫來提高H1N1病毒感染疫苗小鼠的免疫效果和減輕肺部炎癥[54]。皺蓋羅鱗傘（）中純化出一種10 425 Da的蛋白，對甲型流感病毒有抑制作用[55]；純化出的另一種分子量為28 KD的抗病毒蛋白，具有抗甲型流感病毒活性[56]。

4 展 望

很多食用菌在其子實(shí)體、菌絲體和發(fā)酵液中都含有種類繁多的生物活性物質(zhì)[57]。這些食用菌大多可藥食兼用，基于安全性考慮，其所含的天然活性物質(zhì)可作為抗病毒藥物在臨床中大力開發(fā)應(yīng)用?；瘜W(xué)抗病毒藥品毒副作用很大，而且在使用過程中，病毒由于變異會(huì)產(chǎn)生抗藥性。而天然抗病毒藥物不但療效顯著，而且安全性高。因此，人類越來越迫切地需要用天然抗病毒藥物來替代化學(xué)藥物。Li等總結(jié)了治療新型冠狀病毒肺炎COVID-19的潛在藥物，其中包括RdRp的核苷類抑制劑、HCV抑制藥物、蛋白酶抑制劑、凝集素類、免疫調(diào)節(jié)類藥物[58]。這些藥物的類似物在食用菌中廣泛存在。我國采用一些獨(dú)特的中藥方劑對COVID-19的預(yù)防和治療效果足以證明這一點(diǎn)。

人類應(yīng)用藥食用真菌歷史比較悠久，但是多集中在食用和栽培方面，對于其在醫(yī)藥方面的應(yīng)用研究還比較少。雖然我們分離到了一些具有相應(yīng)活性的化學(xué)組分，但是對這些組分的作用機(jī)制還缺乏深刻認(rèn)識(shí)，尤其是高純度單組分及單組分復(fù)配的療效和機(jī)制還沒有進(jìn)一步的研究。雖然上述提到的很多食用菌的活性成分對多種病毒有抗性，但是我們應(yīng)該進(jìn)一步篩選出針對一種病毒的專一高效的食用菌種類和組分，做到治療的精準(zhǔn)性、高效性。已知世界上蕈菌的種類大約有15萬～16萬種，而我們目前認(rèn)識(shí)到的不足10%，有大量的可被開發(fā)利用的菌類等待我們?nèi)ネ诰騕59]。

面對肆虐的病毒，開發(fā)更多有效的天然抗病毒藥物顯得非常重要。大量研究成果已充分證實(shí)，食用菌是天然抗病毒藥物開發(fā)的寶庫。多數(shù)病毒是通過人類的粘膜層入侵人體的[61]。食用菌活性成分能夠通過人體的粘膜層發(fā)揮防護(hù)和清除入侵病毒的作用[60]。這些活性成分通過誘導(dǎo)人體粘膜層的Th1cell，活化其中的Nkcell及細(xì)胞毒性Tcell和Tγδcell，其中Tγδcell擔(dān)負(fù)著非常重要的角色。它一方面能夠發(fā)揮非特異性免疫的作用誘導(dǎo)和趨化白細(xì)胞去吞食入侵的病原體及受病原體侵染的細(xì)胞；另一方面起到呈遞抗原的作用，誘導(dǎo)Bcell向漿細(xì)胞分化，產(chǎn)生相應(yīng)的抗體，啟動(dòng)特異性的體液免疫[62]。COVID-19是通過人的呼吸道黏膜感染人體的。Francesco D P等指出，雖然香菇活性物質(zhì)針對COVID-19的療效尚未進(jìn)行具體評估，但基于其在病毒感染中的保護(hù)作用，可以嘗試將其用于預(yù)防由人類致病性冠狀病毒（包括COVID-19）引起的疾病[62]，以發(fā)揮食用菌活性物質(zhì)在預(yù)防和治療COVID-19中的積極作用。

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Research progress on antiviral effect of active ingredients from mushrooms

Zhang Xiangfeng

( Key Lab. of Microbial Res. Protect. & Devel., Yili Normal Uni., Yining, Xinjiang 835000, China)

Edible mushrooms are rich in bioactive substances, which have anticancer, antibacterial, antiviral, antioxidant and anti-inflammatory effects. Many human diseases are caused by viruses. The side effects of chemical antiviral drugs and the resistance of viruses to existing antiviral drugs require us to develop more natural drugs with high safety. The active components isolated from mushrooms have a significant inhibitory effect on human immunodeficiency virus, influenza, hepatitis B, and hepatitis C virus. To obtain more natural, safe, and effective antiviral drugs, we should conduct more in-depth research on mushrooms.

mushroom; antiviral; human immunodeficiency virus; influenza virus; hepatitis virus

S646

A

2095-0934（2021）03-189-07

微生物資源保護(hù)與開發(fā)利用重點(diǎn)實(shí)驗(yàn)室開放課題（YLUKLM202002）

張相鋒，男，副教授，主要從事微生物多樣性及開發(fā)利用研究工作。E-mail：759737497@ qq.com。