治疗丙肝的天价药Sofosbuvir的作用机制 - sofosbuvir怎样清除丙型肝炎病毒

Sofosbuvir Mechanism of Action - How sofosbuvir fights of Hepatitis C Virus

 

Written by Marko

丙型肝炎一直是一种令人生畏的疾病，死亡人数高，治疗不足。然而，近年来，我们在新发现的名为sofosbuvir的治疗分子的骨架上看到了更成功的治疗方案。

Sofosbuvir是一种抗病毒分子，在结构上类似于现有的抗病毒药物，但它已被证明对丙型肝炎患者有很大益处 - 它几乎单枪匹马一夜之间将治愈率从50％暴涨至95％。这使得以商品名Sovaldi和后来的Harvoni将其推向市场的公司取得了巨大的成功。该分子目前是世界上最畅销的药物成分，因为它在现代丙型肝炎治疗方案中起着重要作用。今天我们来看看sofosbuvir的作用机制。

 

Sofosbuvir作用机制

基本上，sofosbuvir分子通过预防丙型肝炎病毒（HCV）自我复制起作用。复制的必要组分之一是病毒的RNA分子。为了制备新病毒的RNA拷贝，病毒使用一种叫做RNA聚合酶的酶来复制RNA。基本上，在1个现有的RNA分子中，形成了额外的RNA，以便用于构建新病毒并促进丙型肝炎病毒的传播 - 对于患者来说，这意味着丙型肝炎将在他或她的肝脏中表现得越来越多。

 

Sofosbuvir通过抑制酶RNA聚合酶起作用 - 酶聚合酶是执行复制过程的细胞工作者。由于sofosbuvir作用机制无法制造新病毒，现有的丙型肝炎病毒受到患者免疫系统的支配，这种病毒很容易消除病毒。没有sofosbuvir，丙型肝炎病毒有能力重建丢失的病毒并在肝脏中积聚。然而，当sofosbuvir与患者自身的免疫系统结合时，病毒存活的可能性仅为5％（采用适当的治疗方案）。这就是为什么sofosbuvir的成功率为95％。

　

Sofosbuvir作用机制

Sofosbuvir分子的作用机制

以下是sofosbuvir分子在化学术语中的样子。我们将详细解释sofosbuvir的工作原理，换句话说，什么是sofosbuvir作用机制（sofosbuvir MOA）。

Sofosbuvir作为前药（prodrug)

 

Sofosbuvir是一种前药 - 这意味着该分子在人体内化学变为治疗上有用的分子。如果你看结构（右边）;分子的左侧部分保持不变，而围绕P（磷质原子）包围的右侧部分将很容易在体内酶的帮助下变成治疗形式。本质上，核苷酸和核苷二磷酸激酶是两种人类酶，一旦P上的现有基团被切割，它们就将磷酸基团添加到分子中。

 

只有当这个过程从作为前药的sofosbuvir转变为作为药物的sofosbuvir在体内完成时，该分子才成为非常有效的丙型肝炎治疗。

　

Sofosbuvir如何进入丙型肝炎病毒(HCV)

在体内产生的sofosbuvir药物必须进入丙型肝炎病毒，才能有效地破坏HCV复制。这是使sofosbuvir成为有效的丙型肝炎治疗物质的过程。

 

需要提到的是，sofosbuvir不是开箱即用的思维分子。实际上，它与现有的抗病毒分子非常相似，例如阿昔洛韦(acyclovir)，但是一个很小但非常重要的区别。该组治疗剂中的每种抗病毒药物必须具有3个磷酸基团（分子中的Ps）才有效。通常，第一PO 4 -3磷酸基团的添加是最硬的并且因此最慢，然后容易添加另外两个磷酸基团。

　

Sofosbuvir旨在通过使第一个磷酸基团已经附着在其结构上来奇妙地解决这个问题。因此，不需要冗长而艰难的添加组的过程。另外两个磷酸盐基团被迅速加入到sofosbuvir中，所谓的前药现在是一种活性药物。另外的益处还在于与分子的磷酸基团结合的基团 - 这些基团通过掩蔽磷酸基团的负（ - ）电荷并且通过促进Sofosbuvir进入丙型肝炎病毒而起作用。

 

向原药中添加磷酸基团的结果是例外。虽然对大多数抗病毒分子进行了测试，以确定它们能够有效地阻止HCV复制或明显杀死它们，但绝大多数抗病毒分子的效力非常低。添加的磷酸基团将sofosbuvir的作用方式与其他分子分开，以至于我们不仅看到sofosbuvir非常有效;而且它抑制HCV传播的能力是如此巨大，以至于整个疾病开始被认为是易于治疗的 - sofosbuvir已经做了其他已知分子无法做到的事情 - 治愈了95％的丙型肝炎患者。

 

这是一个关于丙型肝炎药物如何起作用的简短视频。

https://fixhepc.com/blog/item/41-sofosbuvir-mechanism-of-action.html

 

Sofosbuvir的作用方式

当在丙型肝炎病毒内部时，sofosbuvir寻找并选择性地附着NS5B聚合酶病毒蛋白，这是病毒复制的重要组成部分。 Sofosbuvir的作用方式是将自己伪装成NS5B的结构部分。这种sofosbuvir作用机制被称为有缺陷的底物。当sofosbuvir与病毒蛋白结合时，它会抑制其进一步构建。因此，蛋白质构建停止，蛋白质不能完成其复制病毒的正常功能。以这种方式，丙型肝炎病毒的数量停滞不前，免疫系统一次一个地杀死它们。如果没有从免疫系统的重大损失中恢复的能力，HCV病毒注定要被消除，这可以治愈丙型肝炎患者（病毒载量变为零）。

这是所有核苷酸样抗病毒药的常规作用机制。对于丙型肝炎治疗，其他药物分子与sofosbuvir一起用于丙型肝炎治疗。 ledipasvir，达卡他韦和利巴韦林的作用机制与sofosbuvir作用机制并不完全不同。一个自然的问题是，如果索非布韦已经是一种具有针对丙型肝炎病毒的先进作用机制的特别有效的药物，为什么丙型肝炎患者必须服用两种或更多种药物分子进行治疗？

　

为什么丙型肝炎总是至少用两种药物分子治疗？

 

Sofosbuvir是一种非常有效的抗丙型肝炎病毒的分子。实际上，sofosbuvir作用机制使其在绝大多数情况下能够消除超过99.99％的病毒。然而，剩下0.01％的病毒仍然构成威胁。

 

这就是为什么使用第二种抗病毒分子来消除可能存活的任何病毒的原因。现代丙型肝炎治疗方案包括主要是sofosbuvir和其次是ledipasvir，达卡他韦或利巴韦林的组合。这就是我们如何确保治疗最佳并将HCV发展为sofosbuvir耐药性的风险降至最低的方法。

 

病毒性疾病的经验告诉我们，受治疗药物威胁的病毒很容易发生突变并变得耐药。没有药物作用机制能够完全消除产生耐药性的可能性。对于耐药性的发展而言特别成问题的是已经用某种药物如sofosbuvir治疗但未全部消除的病毒。也就是说，残留的病毒开发了它们自己的机制，如何最好地对抗药物，使它们抵抗。这就是为什么完全有必要消除与sofosbuvir或任何其他治疗分子接触的所有病毒。

　

Ledipasvir和Daclatasvir作用机制

Ledipasvir与sofosbuvir具有相同的目的 - 防止HCV复制;然而，它采取的方法是不同的。 Ledipasvir作用模式是抑制蛋白质病毒磷蛋白NS5A，其参与病毒复制，组装和分泌。Daclatasvir(达卡他韦)也靶向相同的蛋白质。

　

Sofosbuvir Mechanism of Action - How sofosbuvir fights of Hepatitis C Virus

 

Written by     Marko

　

Hepatitis C has long been a formidable disease with a high death toll and inadequate treatment. However, in the recent years we have seen much more successful treatment options on a backbone of a newly discovered therapeutic molecule called sofosbuvir.

Sofosbuvir is an antiviral molecule, structurally similar to existing antivirals, but it has proven to be of great benefit to Hepatitis C patients - it almost single-handedly skyrocketed the cure rate from 50% to 95% overnight. This has brought the company which brought it to market under the tradename Sovaldi, and later Harvoni, a tremendous success. This molecule is currently the best-selling pharmaceutical ingredient in the world because it plays an essential role in modern Hepatitis C treatment regimen. Today we will have a look at sofosbuvir mechanism of action.

　

How Sofosbuvir Works

Essentially, sofosbuvir molecule works by preventing Hepatitis C virus (HCV) to replicate itself. One of the necessary components for replication is the RNA molecule of the virus. In order to make a copy of RNA for the new virus to form, a virus uses an enzyme called RNA polymerase to replicate RNA. Basically, out of 1 existing RNA molecules, and additional RNA is formed in order to be used to construct a new virus and facilitate the propagation of Hepatitis C virus - which for a patient means Hepatitis C will manifest more and more in his or her liver.

 

Sofosbuvir works by inhibiting enzyme RNA polymerase - the cellular worker that performs the replication process. Being unable to make new viruses due to sofosbuvir mechanism of action, the existing Hepatitis C viruses are at the mercy of patient's immune system which is readily eliminating the virus. Without sofosbuvir, Hepatitis C virus has an ability to rebuilt the lost viruses and build up in the liver. When sofosbuvir, however, is allied with patient's own immune system, there is only a 5% probability that the virus will survive (with appropriate treatment regimen). This is why sofosbuvir has a 95% success rate.

　

Sofosbuvir Mechanism of Action

Sofosbuvir molecule for mechanism of action

Here is how sofosbuvir molecule looks like in chemical terms. We are about to explain in detail how sofosbuvir works or, in other words, what is sofosbuvir mechanism of action (sofosbuvir MOA).

Sofosbuvir as prodrug

 

Sofosbuvir is a prodrug - this means that the molecule is chemically changed to a therapeutically useful molecule in a human body. If you look on the structure (on the right); the left part of the molecule remains unchanged while the right part surrounded around P (phosporous atom) will readily change into a therapeutic form with the help of enzymes in the body. In essence, nucleotidyl and nucleoside diphospate kinases are two human enzymes which add phospatic groups to the molecule once the existing groups on P have been cleaved.

 

Only when this process and transition from sofosbuvir as prodrug to sofosbuvir as drug is done within the body, the molecule becomes a very effective Hepatitis C treatment.

How does Sofosbuvir enter Hepatitis C virus

The created sofosbuvir drug in the body has to enter Hepatitis C virus in order to be effective in disrupting HCV replication. This is the process that makes sofosbuvir stand out as an effective Hepatitis C therapeutical substance.

 

It needs to be mentioned that sofosbuvir is not out-of-the-box thinking molecule. Actually, it is very similar to existing antiviral molecules such as acyclovir for example, but one small but very important difference. Every antiviral in this group of therapeutics has to have 3 phosphate groups (Ps in the molecule) to be effective.  Usually, the addition of the first PO 4 -3  phosphate group is the hardest and thus slowest, the other two phosphate groups are then readily added.

　

acyclovir mechanism of action

Sofosbuvir was designed to marvelously solve this problem by having the first phosphate group already attached to its structure. Thus there is no need for a lengthy and hard process of adding the group. The other two phosphate groups are quickly added to sofosbuvir and the so-called prodrug is now an active drug.  Of additional benefit are also the groups that are bound to the phosphate group of the molecule - these work by masking the negative (-) electric charge of a phosphate group and by that facilitate the entrance of sofosbuvir into the Hepatitis C virus.

 

The results of adding a phosphate group to the original drug is exception. While majority of antiviral molecules were tested to see how effective are they to prevent HCV from either replicating or plain out killing them off, the potency of great majority of them was very low. The added phosphate group separated the mode of action of sofosbuvir from other molecules to such an extent that we don't only see sofosbuvir as very potent; but its ability to suppress HCV spread is so tremendous that the disease as a whole started to be perceived as easily treatable - sofosbuvir had done something no other known molecule was capable of doing - heal 95% of Hepatitis C patients.

 

Here is a short video about how Hepatitis C drugs work.

https://fixhepc.com/blog/item/41-sofosbuvir-mechanism-of-action.html

　

Sofosbuvir mode of action

When inside a Hepatitis C virus, sofosbuvir seeks out and selectively attaches to the NS5B polymerase viral protein which is a vital component virus replication. Sofosbuvir mode of action is to disguise itself as a structural part of NS5B. This sofosbuvir mechanism of action is known as a defective substrate. When sofosbuvir binds to the viral protein, it inhibits its further construction. Thus the protein construction is stopped and the protein cannot complete its normal function of replicating the virus. In such a way, the number of Hepatitis C viruses is stagnating and immune system comes in to kill them off one at a time. Without the ability to recover from the heavy losses against the immune system, HCV virus is doomed to be eliminated, which heals the patient of Hepatitis C (viral load goes to zero).

 

This is a regular mechanism of action of all nucleotide-like antivirals. For Hepatitis C treatment, other drug molecules are used in Hepatitis C treatment together with sofosbuvir. Mechanism of action of ledipasvir, daclatasvir and ribavirin are not altogether different from sofosbuvir mechanism of action. A natural question is why do Hepatitis C patient have to take two or more drug molecules for treatment if sofosbuvir is already such an exceptionally potent drug with an advanced mechanism of action against Hepatitis C virus?

Why is Hepatitis C always treated with at least two drug molecules?

 

Sofosbuvir is an extremely effective molecule working against Hepatitis C virus. In fact, sofosbuvir mechanism of action enables it to eliminate more than 99.99% of the virus in a great majority of cases. However, that 0.01% of the virus left could still prove problematic.

 

This is why a second antiviral molecule is used to eliminate any virus that might have survived. Modern Hepatitis C treatment regimen consist of combination of primarily sofosbuvir, and secondarily ledipasvir, daclatasvir or ribavirin. This is how we can ensure that the treatment is optimal and minimize the risk of HPV developing sofosbuvir drug resistance.

 

Experience with viral disease has taught us that virus, which is being endangered with therapeutic drugs, readily mutates and becomes drug-resistant. No drug mechanism of action is capable of completely eliminating the possibility of drug-resistance arising. Especially problematic for the development of drug resistance are viruses that have been treated with a certain drug like sofosbuvir but were not all eliminated. Namely, the remaining ones developed their own mechanism of how to best survive against the drug, rendering them resistant. This is why it is utterly necessary to eliminate all the virus that has come into contact with sofosbuvir or any other therapeutic molecule.

Ledipasvir and Daclatasvir Mechanism of Action

Ledipasvir has the same aim as sofosbuvir - to prevent HCV from replicating; however, the approach it takes is different. Ledipasvir mode of action is to inhibit protein  viral phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion. The same protein is also targeted by daclatasvir.

 

Sofosbuvir Mechanism of Action - How sofosbuvir fights of Hepatitis C Virus  https://fixhepc.com/blog/item/41-sofosbuvir-mechanism-of-action.html