Erythrocyte G protein as a novel target for malarial chemotherapy.
Erythrocyte G protein as a novel target for malarial chemotherapy.
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红细胞G蛋白是疟疾化学疗法的新靶标。
DOI：
10.1371/journal.pmed.0030528
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发表时间：
2006-12
期刊：
影响因子：
15.8
通讯作者：
Haldar, Kasturi
中科院分区：
文献类型：
--
作者：
Murphy, Sean C.;Harrison, Travis;Hamm, Heidi E.;Lomasney, Jon W.;Mohandas, Narla;Haldar, Kasturi
疟疾仍然是一个严重的健康问题，因为当寄生虫目标发生突变时，所有目前使用的药物都会产生耐药性。迫切需要新的抗疟药物靶点来降低全球发病率和死亡率。我们之前的结果表明，抑制红细胞 Gs 信号传导可以阻止人类疟原虫恶性疟原虫的入侵。 我们研究了红细胞鸟嘌呤核苷酸调节蛋白 Gs 作为新型抗疟靶点。红细胞“幽灵”装载有旨在阻断 Gs 与其受体相互作用的 Gs 肽，在 β-肾上腺素能激动剂诱导的信号传导中被阻断。这一发现直接表明红细胞 Gs 具有功能性，普萘洛尔（G 蛋白偶联 β-肾上腺素受体拮抗剂）可抑制红细胞中的 Gs 活性。我们随后使用 Ghost 系统将宿主 G 的抑制与寄生虫进入直接联系起来。此外，我们发现负载该肽的幽灵在细胞内寄生虫的成熟中受到抑制。与其他 β2 拮抗剂一样，普萘洛尔也能抑制血液阶段寄生虫的生长。 β-阻滞剂生长抑制似乎是由于裂殖体终末期的延迟所致。当在细胞培养中与现有抗疟药联合使用时，普萘洛尔可将现有药物对恶性疟原虫的 50% 和 90% 抑制浓度降低 5 至 10 倍，并且还可有效减少动物感染模型中的药物剂量。这些数据共同表明，除了侵袭之外，细胞内寄生虫增殖还需要红细胞 G 蛋白信号传导，因此可能成为一种新的抗疟靶点。这些结果证明了红细胞 Gs 拮抗作用提供了一种对抗感染的新策略，并且有潜力用于开发与现有抗疟药的联合疗法。红细胞 G 蛋白信号传导是细胞内疟疾寄生虫增殖所必需的，因此可能成为一种新的抗疟靶点。迫切需要治疗疟疾的新药物，因为疟原虫已经对几乎所有类型的常用药物产生了耐药性。当一个人被感染疟疾的蚊子叮咬时，寄生虫首先感染人的肝细胞，然后继续感染红细胞，寄生虫在红细胞中繁殖并发育成称为裂殖体的寄生虫阶段。然后红细胞破裂并向血液中释放更多的裂殖体；正是人类感染的这个“血液阶段”导致了疾病症状。因此，开发抗疟疾新药的努力通常集中在感染的“血液阶段”。开发新药的一种策略被称为“宿主靶向”方法。这意味着，与其试图阻止寄生虫本身内部发生的过程，不如开发一种药物来阻止人红细胞内发生的过程，否则寄生虫将需要这种药物来完成其生命周期。疟疾寄生虫很难对这种药物产生耐药性，因为人的红细胞的变化比寄生虫本身的变化要慢得多。该研究小组一直在研究人类红细胞内的一系列分子过程，这似乎是疟疾寄生虫进入细胞所必需的。他们希望更好地了解这些过程，特别是找出是否可以使用特定分子来阻断这些过程，并通过这样做来防止疟疾寄生虫进入红细胞并在红细胞内繁殖。特别是，当疟疾寄生虫侵入红细胞时，它们会在红细胞周围形成膜，其中含有从红细胞膜“劫持”的脂质和蛋白质。这些研究人员已经知道两种特定的蛋白质是通过这种方式被劫持的： β2-肾上腺素能受体（β2-AR）和异三聚体 G 蛋白（Gs）。这两种蛋白质共同作用，将信息穿过膜表面传递到细胞内部。小分子可用于阻断通过 β2-AR 和 G 的信号传导，因此有可能提供一种防止疟疾寄生虫进入红细胞并在其中繁殖的新方法。首先，研究人员制造了红细胞“幽灵”来研究这些分子过程。这意味着他们从健康的人类志愿者身上取出新鲜的红细胞，将其破裂以除去一半的内容物，并在重新密封细胞膜之前将其装载上标记物和其他物质。这些重新密封的标记和货物使他们能够看到细胞内发生的情况。疟疾寄生虫能够正常侵入这些幽灵并在其中繁殖。当研究人员引入一种特定的肽（一种由一系列短氨基酸组成的分子）时，他们发现它可以阻断幽灵体内的 Gs 信号传导。这种肽还可以防止疟疾寄生虫在鬼体内发育。因此，他们得出结论，红细胞内的 Gs 信号传导对于寄生虫的生命周期很重要。研究人员随后检查了一种名为普萘洛尔的药物，已知该药物可作用于 Gs 信号传导，并且通常用于治疗高血压。当以特定浓度使用时，这种药物还可以阻止鬼体内疟疾寄生虫的生长。最后，研究人员研究了普萘洛尔和其他抗疟药物对培养皿中的人类疟原虫以及注射了感染啮齿动物的疟原虫的小鼠的影响。在这些实验中，添加普萘洛尔减少了有效治疗组织培养和小鼠疟疾感染所需的其他“寄生虫靶向”药物的用量。表明 Gs 信号通路对于疟疾寄生虫的生命周期很重要，这为药物开发开辟了新的可能性。具体来说，普萘洛尔（已被批准用于治疗高血压和其他疾病）本身可能提供一种新的候选疗法，无论是单独使用还是与现有药物联合使用。然而，这些组合首先需要在人体临床试验中进行测试，也许是通过观察它们是否对对现有抗疟药物没有反应的人具有抗疟活性。由于它可以降低血压，而某些疟疾患者的血压已经很低，因此有人担心普萘洛尔可能不是合适的候选药物，尤其是现有的也能降低血压的抗疟药物。然而，如果普萘洛尔被证明不是理想的候选药物，则可以测试其他阻断 Gs 信号传导的分子的抗疟活性。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0030528。世界卫生组织发布了一个迷你网站，其中包含有关全球疟疾各个方面的信息链接，包括治疗、预防和当前的疟疾控制计划 Medicines for Malaria Venture 是公共和私人组织（包括制药行业）之间的合作项目，旨在资助和管理用于治疗和预防疟疾的新药的开发 药物发现和药物开发的维基百科条目（维基百科是一个互联网） 任何人都可以编辑的百科全书）
Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte Gs signaling blocked invasion by the human malaria parasite Plasmodium falciparum. We investigated the erythrocyte guanine nucleotide regulatory protein Gs as a novel antimalarial target. Erythrocyte “ghosts” loaded with a Gs peptide designed to block Gs interaction with its receptors, were blocked in β-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte Gs is functional and that propranolol, an antagonist of G protein–coupled β-adrenergic receptors, dampens Gs activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host Gs to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other β2-antagonists. β-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection. Together these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte Gs antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials. Erythrocyte G protein signaling is needed for intracellular malarial parasite proliferation and thus may present a novel antimalarial target. New drugs for treatment of malaria are urgently needed, because the malaria parasite has evolved resistance against virtually all types of commonly used drugs. When a person is bitten by a malaria-infected mosquito, the parasite first infects the person's liver cells before going on to infect red blood cells, where the parasites multiply and develop into a parasite stage called a schizont. The red blood cells then burst and release more schizonts into the bloodstream; it is this “blood stage” of infection in humans that causes the symptoms of disease. Therefore efforts to develop new drugs against malaria often focus on this “blood stage” of infection. One strategy for developing new drugs is termed the “host-targeted” approach. This means that rather than trying to block processes occurring within the parasite itself, a drug can be developed which blocks processes within the person's red blood cells, and which would otherwise be needed for the parasite to complete its life cycle. It will be difficult for malaria parasites to evolve resistance to such a drug, because changes in a person's red blood cells occur much more slowly than in the parasites themselves. This research group has been studying a set of molecular processes within human red blood cells which seemed to be required for entry of malaria parasites into the cells. They wanted to get a better understanding of those processes and, specifically, to find out whether it would be possible to use particular molecules to block those processes, and by doing so to prevent malaria parasites from entering and multiplying within red blood cells. In particular, when the malaria parasites invade the red blood cell, they form membranes around the red blood cell, containing lipids and proteins “hijacked” from the red blood cell membrane. These researchers already knew that two particular proteins were hijacked in this way; the β2-adrenergic receptor (β2-AR) and heterotrimeric G protein (Gs). These two proteins act together to pass messages across the surface of the membrane to inside the cell. Small molecules could be used to block signaling through β2-AR and Gs, and therefore potentially to provide a new way of preventing malaria parasites from entering red blood cells and multiplying within them. Firstly, the researchers made red blood cell “ghosts” in which to study these molecular processes. This meant that they took fresh red blood cells from healthy human volunteers, burst them to remove half the contents and loaded them with markers and other cargoes before resealing the membranes of the cell. These resealed markers and cargoes allowed them to see what was happening inside the cells. Malaria parasites were able to invade these ghosts normally and multiply within them. When the researchers introduced a specific peptide (a molecule consisting of a short series of amino acids), they found that it blocked Gs signaling within the ghosts. This peptide also prevented malaria parasites from developing inside the ghosts. Therefore, they concluded that Gs signaling inside the red blood cell was important for the parasite life cycle. The researchers then examined a drug called propranolol which is already known to act on Gs signaling and which is commonly prescribed for high blood pressure. This drug also blocked development of malaria parasites inside the ghosts when used at a particular concentration. Finally, the researchers studied the effect of giving propranolol, along with other antimalarial drugs, to human malaria parasites in a culture dish and to mice injected with a malaria parasite that infects rodents. In these experiments, adding propranolol reduced the amount of other “parasite-targeted” drugs that were needed to effectively treat malarial infection in tissue culture and in mice. Showing that the Gs signaling pathway is important for the malaria parasite's life cycle opens up new possibilities for drug development. Specifically, propranolol (which is already approved for treatment of high blood pressure and other conditions) might itself provide a new candidate therapy, either alone or in combination with existing drugs. These combinations would first, however, need to be tested in human clinical trials, perhaps by seeing whether they have antimalarial activity in people who have not responded to existing antimalarial drugs. Since it acts to lower blood pressure, which can already be low in some people with malaria, there are some concerns that propranolol might not be a suitable drug candidate for use, especially with existing antimalarial drugs that also reduce blood pressure. However, other molecules which block Gs signaling could be tested for activity against malaria should propranolol prove not to be an ideal drug candidate. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030528. The World Health Organization publishes a minisite containing links to information about all aspects of malaria worldwide, including treatment, prevention, and current programs for malaria control Medicines for Malaria Venture is a collaboration between public and private organizations (including the pharmaceutical industry) that aims to fund and manage the development of new drugs for treatment and prevention of malaria Wikipedia entries for drug discovery and drug development (Wikipedia is an internet encyclopedia that anyone can edit)
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影响因子：
6.5
作者：
DLUZEWSKI, AR;RANGACHARI, K;GRATZER, WB
通讯作者：
GRATZER, WB
影响因子：
4.8
作者：
Hiller, NL;Akompong, T;Haldar, K
通讯作者：
Haldar, K
DOI：
10.1073/pnas.2133080100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Lopez-Estraño, C;Bhattacharjee, S;Haldar, K
通讯作者：
Haldar, K
影响因子：
13.6
作者：
Krishna S;Woodrow CJ;Staines HM;Haynes RK;Mercereau-Puijalon O
通讯作者：
Mercereau-Puijalon O
影响因子：
56.9
作者：
Harrison, T;Samuel, BU;Haldar, K
通讯作者：
Haldar, K