Today, tomorrow, learn English naturally. 天天自然学英语
Peptide breakthrough paves way for oral treatment of disease
Peptide therapeutics have revolutionized the treatment of disease, but their characteristics typically restrict them to administration by injection. Now, researchers have succeeded in creating an oral peptide, which has the potential to usher in a new era in drug development.
Comprised of short chains of amino acids, naturally occurring peptides serve many functions, including acting as hormones, growth factors, and neurotransmitters. They also play an important role in pharmaceuticals. Peptide therapeutics commonly mimic their naturally occurring counterparts to provide life-saving treatment. The injectable insulin used by diabetics is just one example.
Peptide therapeutics have inherent advantages: high potency and selectivity and good efficacy, safety, and tolerability. However, there are downsides when it comes to oral administration. Most peptide therapeutics are large molecules, degrade in the harsh environment of the gut and most often can’t cross cell membranes, necessitating their administration by injection. By comparison, many oral drugs are small molecules with simple chemical structures, so they easily diffuse across cell membranes to reach their intracellular target, producing more predictable therapeutic effects.
But in a new study, researchers from Switzerland’s École Polytechnique Fédérale de Lausanne (EPFL) achieved a major milestone in drug development: creating a novel peptide that may overcome the problems associated with oral administration.
“There are many diseases for which the targets were identified, but drugs binding and reaching them could not be developed,” said Christian Heinis, corresponding author of the study. “Most of them are types of cancer, and many targets in these cancers are protein-protein interactions that are important for the tumor growth but cannot be inhibited.”
As an aside, biological activities are regulated through protein complexes, typically controlled via protein-protein interactions (PPIs). Studies have associated aberrant PPIs with various diseases, including cancer, infectious and neurodegenerative diseases. Since classic drug targets are usually enzymes, ion channels, or receptors, targeting PPIs is an essential strategy for the development of new drugs.
Building upon their previous research to develop a ‘peptide pill’, the EPFL team turned their sights to cyclic peptides, which can bind to challenging disease targets with high affinity and specificity. But, like existing peptide therapeutics, they’re subject to the same problems in terms of oral administration.
“Cyclic peptides are of great interest for drug development as these molecules can bind to difficult targets for which it has been challenging to generate drugs using established methods,” Heinis said. “But the cyclic peptides cannot usually be administered orally – as a pill – which limits their application enormously.”
Undeterred, the researchers developed a two-step strategy to synthesize cyclic peptides that would remain stable when taken orally. The first step was synthesizing linear peptides and subjecting them to cyclization so they formed ring-like chemical structures connected by a metabolically stable thioether (carbon-sulfur-carbon) bond. Thioethers are present in some amino acids and can be created in the lab by the reaction of a thiol with a base and an electrophile, an electron-deficient molecule or atom that’s happy to take electrons from another one to make a new covalent bond. In step two, the cyclized peptides underwent the process of acylation, which attaches carboxylic acids to them to diversify their molecular structure further.
The process occurred in the same reactive container – referred to as one-pot synthesis – which eliminated the need for intermediate purification steps and allowed for high-throughput screening directly in the synthesis plates. The researchers targeted the enzyme thrombin, a critical disease target because of its central role in blood clotting and, therefore, thrombotic disorders like strokes and heart attacks. Using the one-pot method, they synthesized a comprehensive library of 8,448 cyclic peptides with an average molecular mass of about 650 daltons (Da), just slightly above the cutoff of 500 Da recommended for orally administered small molecules. They then screened their library of peptides against the disease target thrombin.
The researchers tested their thrombin-inhibiting cyclic peptides on rats. They showed an oral bioavailability of up to 18%, meaning that 18% of the drug entered the bloodstream and had a therapeutic effect when administered orally. While it might not sound particularly impressive, consider that orally administered cyclic peptides generally show a bioavailability of below 2%. The researchers say it’s a significant advancement for biologic drugs, including peptides.
“We have now succeeded in generating cyclic peptides that bind to a disease target of our choice and can also be administered orally,” said Heinis. “To this end, we have developed a new method in which thousands of small cyclic peptides with random sequences are chemically synthesized on a nanoscale and examined in a high-throughput process.”
The study’s results have opened up the possibility of treating a range of diseases that, until now, have been a challenge to address using oral drugs. The versatility of the one-pot synthesis method means that it can be adapted to target a wide range of proteins, potentially leading to breakthroughs in areas where medical needs are currently unmet.
“To apply the method to more challenging disease targets, such as protein-protein interactions, larger libraries will likely need to be synthesized and studied,” said Manuel Merz, the study’s lead author. “By automating further steps of the methods, libraries with more than one million molecules seem to be within reach.”
The next step for the researchers is to target several PPIs. They’re confident they can develop orally administered cyclic peptides for at least some of them.
注释：
Peptide: n
表示" 肽"，如：A peptide contains many molecules of amino acids, typically between 10 and 100. 多肽是一种含有许多氨基酸分子的肽，主要是处于10到100之间。
usher: v
表示" 引导；引入"，means "take (someone) to their seats, as in theaters or auditoriums"，如：The key is to create a critical mass of leaders to usher in change. 这一切的关键在于，要培养出数量足够庞大的领导人来引导变革。
neurotransmitter: n
表示"神经递质"，如：Neurotransmitter synthetise needs trace and constant elements. 神经递质的合成需要微量元素及常量元素。
efficacy: n
表示" 功效"，means "capacity or power to produce a desired effect"，如：We are testing the efficacy of a new drug. 我们正在测试新药的功效。
membrane: n
表示"【C】薄膜"，means "a thin pliable sheet of material"，如：A vibrating membrane in the ear helps to convey sounds to the brain. 耳膜的振动帮助声音传送到大脑。
necessitate: v
表示" 使 ... 成为必需；迫使"，means "make necessary"，如：Your proposal will necessitate borrowing more money. 依你的建议就必须增加借款。
intracellular: adj
表示" 细胞内的"，means "located or occurring within a cell or cells"，如：Viruses are obligate intracellular parasites. 病毒是专性的细胞内寄生物。
inhibit: v
表示" 抑制；阻止"，如：You should inhibit wrong desires and impulses. 你应当抑制不正当的欲望和行动。
aside: n
表示" 旁白；离题话"，means " remark that is not directly connected with the main subject that is being discussed"，如：This is surely an author's aside. 这当然是作者的旁白。He spoke in an aside of his family. 他离开本题谈起他的家庭。
aberrant: adj
表示"脱离常轨的；变体的；畸变的"，means "changed from what is usual"，如：One person can evolve in individual actions, no matter how aberrant. 一个人在他的个人活动中的行为会发展，不管其人的个人行为是如何越出常轨。
affinity: n
表示"密切关系；吸引力"，means "state of relationship between organisms or groups of organisms resulting in resemblance in structure or structural parts;"，如：He is not an impartial witness because of his affinity with the accused. 他不是公正的见证人,因为他与被告有姻亲关系。
specificity: n
表示"特殊性；专一性"，means "the quality of being specific rather than general"，如：Again, the specificity rule cuts against the tariff. 再者，特效法则也排斥关税。
Undeterred: adj
表示"未受阻的；未受挫折的"，means "not deterred"，如：They are also largely undeterred by disapproval. 他们基本上对别人的劝阻无动于衷。
cyclization: n
表示" 环合"，如：Cyclization occurs readily with dilute alkali. 遇到稀碱就容易环化。cyclization process 环化过程
thioether: n
表示" 硫醚"，如：The effect of reaction temperature of the formation on thioether dianhydride monomer was discussed. 讨论了温度对硫醚二酐形成的影响。
electrophile: n
表示" 亲电子试剂"，如：Electrophile chemical pollutants 亲电性化学污染物
covalent: adj
表示" 共有原子价的；共价的"，means "of or relating to or characterized by covalence"，如：In covalent bonding,atoms share electrons. 在共价键中，原子共有电子。
acylation: n
表示" 酰化作用"，如：An example of the acyl group is the acetyl group. 乙酰基是酰基的一个例子。
throughput: n
表示" 产量；吞吐量"，如：The average daily throughput was 1, 370 tons of ore. 日平均产量为一千三百七十吨矿砂。
cutoff: n
表示" 近路；切断"，如：The amendments provide several other sanctions, including a cutoff of federal highway funds. 修正案提供了几种其他制裁，其中包括中止联邦公路资金。
thrombin: n
表示" [生化]凝血酵素"，means "an enzyme that acts on fibrinogen in blood causing it to clot"，如：A plasma protein that is converted into thrombin during blood clotting. 凝血原酶一种血浆蛋白质，在血液凝聚时转化成凝血酵素
bioavailability: n
表示"生物利用度"，means ""，如：Bioavailability expresses the extent of drug absorption into the systemic circulation. 生物利用度表示药物吸收进入体循环的分量。
nanoscale: n
表示"纳尺度"，如：Nanoscale systems are so small that this assumption breaks down completely. 但是奈米系统太小了，以上的前提完全不能成立。
中文简要说明：
胜肽(Peptide)是一种短链氨基酸组成，具有多种功能，包括充当激素、生长因子和神经传导物质。胰岛素就是一种胜肽，几十年来，胜肽疗法已攻克了许多难缠的慢性病。然而目前的胜肽都是注射液，使用上仍有不便与难保存之处。现在，研究人员已经地创造了一种口服胜肽，将是药物开发的新里程碑。
新阿特拉斯(New Altas)报导，胜肽疗法具有很多先天优势：高效、选择性强、疗效好、安全性佳、耐受性佳。然而，因为目前合成的胜肽分子，属于长链大分子，如果采用口服，就会被胃液与肠液的恶劣环境中降解，即使没有被分解，大分子也无法穿过小肠壁的细胞膜，因此目前只能采用注射给药。
但在瑞士洛桑联邦理工学院 (EPFL) 的研究人员，刚刚创造出一种新型的短链小分子胜肽，这将可以采用口服给药的方式。
该研究的作者海尼斯博士(Christian Heinis）表示：「许多癌症的『标靶』已被确定，但先前的困境是，无法开发出击中这些靶目标药物。」
「所谓的『标靶』，是指细胞内的指令传导机制，那也是蛋白质胞器的相互作用(PPI)。虽然我们已知道原理，但无法被抑制。」
顺便说一句，目前对PPI的研究已愈来愈深入，开始了解许多疾病就是PPI的指令错误造成的，包括癌症、传染病和神经退化性疾病。现行的标靶药物通常是酵素、离子通道或受体，因此对标PPI 将是教新药开发的重要策略。
目前的胜肽研究，已将目光转向了分子链较小的环肽(cyclic peptide)，这是一种具有高亲和力的特质，与那些具有挑战性的疾病标靶相结合。但是，与现有的胜肽疗法一样，环肽也不能口服，不然会降解被破坏。
但是研究人员并没有被难住，他们利用代谢仍可稳定的硫醚（碳-硫-碳）键连接环状化学结构。硫醚本身存在于某些胺基酸中，它们的特色是保持原样的能力很强，即使被分解到缺了电子，仍然很容易从环境中抓回电子以形成新的共价键。以这个特质为基础，将环肽附着在这个结构上，就能实现口服仍然有效的环肽药。
研究人员以该方法制作出口服式凝血酶环肽，并在大鼠身上测试，经过验血检查，有服用量的18%凝血酶进入血液中，并产生治疗效果。虽然18%听起来可能不是特别好的成绩，多数的成分仍然失去效用了。但要知道，在此之前开发的口服环肽，其医疗效果通常低于 2%，就知道这绝对是一个重大进步。
研究人员的下一步是开发其他的标靶药物，他们相信包括免疫型疾病、糖尿病，或是癌症的治疗，都能因此获得新的效能口服药物。
留言微信公众号《自然学英语LearnNaturally》，可咨询更多！