據(jù)物理學(xué)家組織網(wǎng)5月14日?qǐng)?bào)道,，一個(gè)國(guó)際研究小組基于自然產(chǎn)生的C3a肽,，研制出了一種候選藥物,。C3a肽是調(diào)節(jié)免疫反應(yīng)的核心成員,，能夠增強(qiáng)或阻止其活動(dòng)影響的藥物或?qū)⒂兄谥委熛?、?lèi)風(fēng)濕性關(guān)節(jié)炎和敗血癥等多種炎癥性疾病,。相關(guān)研究報(bào)告發(fā)表在近期出版的《藥物化學(xué)雜志》上。
研究團(tuán)隊(duì)首先創(chuàng)建了名為C3a受體蛋白質(zhì)的三維結(jié)構(gòu)圖,，該蛋白位于人體細(xì)胞的表面,，并在調(diào)節(jié)免疫系統(tǒng)下屬的補(bǔ)體系統(tǒng)中發(fā)揮著關(guān)鍵作用。
對(duì)于補(bǔ)體系統(tǒng)的調(diào)節(jié),，被認(rèn)為是一種控制過(guò)于活躍的或因出錯(cuò)而致害的免疫反應(yīng)的可能途徑,。然而，幾乎沒(méi)有藥物能直接定位補(bǔ)體蛋白,，也沒(méi)有藥物能定位C3a受體,。這在某種程度上是因?yàn)檠a(bǔ)體系統(tǒng)十分復(fù)雜，其有時(shí)候能淡化免疫反應(yīng),，而其他時(shí)候卻能激起更強(qiáng)烈的反應(yīng),。
隨后，科學(xué)家利用計(jì)算技術(shù)設(shè)計(jì)出了能增強(qiáng)或阻止C3a活動(dòng)的新型肽,，因?yàn)樗麄冾A(yù)測(cè)這些肽將與受體發(fā)生反應(yīng),，以阻止或增強(qiáng)它們的活性。他們計(jì)算出蛋白質(zhì)的三維結(jié)構(gòu)會(huì)如何改變,，以及什么時(shí)候會(huì)在蛋白質(zhì)的化學(xué)序列中發(fā)生改變,。基于自然產(chǎn)生的,、通常能夠調(diào)節(jié)人體細(xì)胞中C3a受體的C3a肽的三維結(jié)構(gòu),，研究人員制成了針對(duì)C3a活性的對(duì)抗劑和興奮劑，其具備前所未有的效能和精確度,。這種將肽設(shè)計(jì)為所需形狀的能力,，允許科學(xué)家能以精確的方式定位C3a受體。最后,，科研人員在小鼠細(xì)胞和人體細(xì)胞內(nèi)對(duì)肽進(jìn)行了測(cè)試和分析,，證實(shí)其與此前的理論預(yù)測(cè)相符。
除了有助于治療哮喘、類(lèi)風(fēng)濕性關(guān)節(jié)炎和敗血癥等多種炎癥性疾病,，通過(guò)對(duì)補(bǔ)體的調(diào)控還有望治療再灌注損傷,。其通常發(fā)生在體內(nèi)的血流被短暫切斷時(shí)，例如心臟病發(fā)作或中風(fēng),，血液回流時(shí)產(chǎn)生的炎癥反應(yīng),。另一種可能的應(yīng)用是器官移植，該種情況下,，身體通常會(huì)作出破壞性的免疫反應(yīng),，來(lái)對(duì)抗新引入的器官。
研究團(tuán)隊(duì)下一步將在具有炎癥的活體動(dòng)物模型上測(cè)試制成的新肽,，他們還計(jì)劃更深入地探索C3a在炎癥中扮演的雙重角色,，并力圖開(kāi)發(fā)更多的候選藥物。(生物谷：Bioon.com)
doi:10.1021/jm201609k
PMC:
PMID:
De Novo Peptide Design with C3a Receptor Agonist and Antagonist Activities: Theoretical Predictions and Experimental Validation
Meghan L. Bellows-Peterson, Ho Ki Fung, and Christodoulos A. Floudas
Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two- stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC50 values of 25.3 and 66.2 nM) and two others were partial agonists (IC50 values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists.
