将大自然的病毒战斗机变成强大的药物：合成的“肽”来治愈疾病

Antimicrobial peptides fight viral diseases but a structural flaw makes them difficult to use as drugs. A deft molecular fix could create synthetic “peptoids” to cure diseases.

Among the powerful biochemicals of the human immune system, peptides are one of the best.

Most commonly found in the places where microbes love to take root – mucous membranes of the eye, mouth, nose, and lungs – they’re known to kill all sorts of tiny invaders, such as viruses, bacteria, and fungi.

Given their power, one might think peptides would represent promising drug treatments, perhaps even a cure, for many infectious diseases. But, alas, they are fundamentally flawed: They are vulnerable to a myriad of enzymes whose job is to rapidly break them down in a way that robs them of their therapeutic properties.

“由于它们易受酶促分解的脆弱性，肽不是理想的药物。它们的生产成本很高，但是必须大量剂量，因为它们会如此迅速地分解。”斯坦福大学工程学院生物工程副教授Annelise Barron说。

但是，正如巴伦（Barron）在期刊上所描述的那样Pharmaceuticals, she and a team of collaborators have now created peptide-like molecules – which she calls “peptoids” – that could circumvent peptides’ shortcomings and turn these new molecules into the basis for an emerging category of antiviral drugs that could treat everything from herpes and COVID-19 to the common cold. Although Barron cautions that years of development and testing remain before these peptoid-based drugs will make it to market, results to date are extremely encouraging.

A better backbone

肽是一种被称为“仿生学”的生化类型 - 模仿生物分子的行为，但具有某些关键优势。

它们的现实世界对应物，肽，由一系列生物活性氨基酸组成，称为侧链，以特异性序列键合到长链支架，称为肽主链。结果有点像生物分子魅力手镯。不幸的是，将所有重要魅力的键太容易被称为蛋白酶（消化蛋白质的蛋白酶）溶解在体内。当肽溶解时，它们的力量消失了。

但是，肽是为了耐用性而设计的。它们的力量源于它们的结构，就像肽的结构一样，但与肽的结构有根本不同。通过改变基础的骨干并加强将魅力固定在适当的纽带，巴伦的团队为这些抗病毒剂创造了一种方法，以保留肽在被蛋白酶降解时损失的力量。

巴伦说：“我们很兴奋，我们的肽作为新型抗病毒药表现出很大的潜力。”

上升潜力

In their study, Barron and team chose to focus on the herpes virus, which is most notable for causing cold sores around the mouth, sexually transmitted infections and even certain forms of blindness. If contracted later in life, herpes can be particularly devastating to its host. Herpes virus brain infections also are associated with Alzheimer’s disease, an active area of research.

The team reviewed a number of prospective peptoids, beginning with a library of 120 molecular structures – which were at that point just chemical symbols on a page. Based on preliminary experiments, they narrowed these to 10 promising candidates, which her team synthesized. Barron then worked with professor Gill Diamond (University of Louisville) to test her newly minted molecules not just for their effectiveness against the herpes virus, but also for their effect on healthy human cells from the exterior surface of the mouth – known as the oral epithelium.

As expected, some of the peptoids showed no effect against the virus. Others were active, but harmful to healthy host cells. But a precious handful of five peptoids proved worthy of additional study. In the end, two hit the sweet spot – defanging the herpes virus while not harming epithelial cells. One of the candidates, in fact, showed “complete” effectiveness against the virus, and that has Barron excited about the possibilities for treating herpes and, perhaps, beyond.

破裂泡沫

肽通过破坏病毒封闭的外膜来起作用。这种保护性气泡是任何病毒将自己浸入健康组织并将其有害DNA分配到人类细胞中的能力的关键，从而导致感染。

“肽可以破坏膜，不仅是疱疹，而且还破坏了其他病毒。这应该给他们广泛的适用性，甚至可能针对某些目前无法治愈的致命病毒感染。”巴伦说。

Barron has since sent samples of peptoids to infectious disease labs around the world asking them to test these new structures against a host of virulent strains, most notably the SARS-CoV-2 virus that causes COVID-19, but also more familiar viruses like influenza and rhinovirus, the culprit behind the common cold.

巴伦说：“我合作者的早期报道非常令人鼓舞。”“因为我们的肽模仿了一种非常特定的人类广谱抗病毒肽-Cathelicidin LL-37 - 我们对它们起作用并不感到惊讶，但仍然非常高兴看到这些结果来自世界各地。”

Reference: “Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids” by Gill Diamond, Natalia Molchanova, Claudine Herlan, John A. Fortkort, Jennifer S. Lin, Erika Figgins, Nathen Bopp, Lisa K. Ryan, Donghoon Chung, Robert Scott Adcock, Michael Sherman and Annelise E. Barron, 31 March 2021,Pharmaceuticals。
DOI: 10.3390/ph14040304