A Multi-Center Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Maraviroc and Atorvastatin for the Treatment of Subjects With Long COVID/Post-Acute Sequalae of Covid (PASC)

The IMPACT Long Covid Treatment clinical study (IMPACT-LC) is testing two repurposed and previously approved drugs, Maraviroc and Atorvastatin, for the treatment of non-hospitalized subjects with long COVID/Post-Acute Sequelae of COVID (PASC). The main goals of the clinical study are to determine if this combination drug therapy can improve neurocognitive and physical functions in Long Covid patients, such as fatigue severity, heart rate, blood pressure, digestion, breathing, dizziness, and cognitive function. A secondary goal is to determine if biomarker levels, measured by a diagnostic test, can improve during treatment. To qualify for the trial, a subject must be an adult ≥ 18 and ≤ 65 years of age and meets the WHO-defined post-COVID-19 condition and has one or more new-onset Long Covid symptom that persist ≥ 6 months after the diagnosis of acute COVID-19 infection. A total of 252 participants will take either two daily doses of two existing medications (Maraviroc and Atorvastatin together as separate tablets) or a placebo (pills with no active ingredient) for 16 weeks. Although these medications are not yet approved for Long Covid, they are FDA-approved for use in treating other health conditions.

开始日期2025-09-01

申办/合作机构-

NCT06853223

/ Not yet recruiting临床2期IIT

A Randomized Trial of CCR5 Inhibition as a Complement to Lung Transplant Induction Immunosuppression

Lung transplant recipient survival lags other solid organ recipients, with the main early cause of death being primary graft dysfunction (PGD). PGD occurs in up to 1/3 of all recipients, is driven by the body's innate immune response, and has no known medical therapies for treatment or prevention. Investigators have recently shown that Natural Killer (NK) cells, a key innate immune cell, are critical in causing PGD. Importantly, the investigators found that Maraviroc, an FDA-approved drug that works to inhibit these immune cells, prevented lung injury in mouse models of PGD.
The goal of this clinical trial is to learn if Maraviroc works to treat PGD in Lung Transplant patients who are above the age of 18 and have a PGD risk score greater than 50%. The objectives the study hopes to address are:
To address the safety and tolerability of Maraviroc. To test a strategy for PGD enrichment in a lung transplant population. To measure the efficacy and biological efficacy of using Maraviroc. To study the biochemical, physiologic, and molecular effects of the drug on the body.
This will be a double blind study where patients will either get the Maraviroc drug or a placebo. Researchers will then compare the two groups to address the above objectives.
Participants will:
Take drug Maraviroc or a placebo every 12 hours for 3 days post surgery. Follow up will occur during the entire length of stay at UCSF, about 16 days, with a single 12 month follow up once released.

开始日期2025-06-01

申办/合作机构

The University of California, San Francisco

[+1]

NCT06805656

/ Not yet recruitingN/A

Multi Interventional Approaches to Mitigate HIV Reservoirs Aiming the Sustained HIV Remission Without Use of Antiretrovirals

A modern and urgent challenge in fighting HIV infection is to achieve sustained HIV remission without the use of antiretrovirals. The investigators' preliminary data indicate that the use of combined strategies to mitigate the HIV proviral reservoir size among individuals with suppressive antiretroviral treatment achieved unprecedented results in the reduction of HIV DNA present in these cells and in the reduction of CD4 + and CD8 + T cell activation. Combined interventions include intensified antiretroviral treatment to mitigate residual HIV replication, use of a histone deacetylase inhibitor to interrupt viral latency, use of an anti-proliferative medication to reduce long-lived T cells that harbor HIV and a personalized dendritic cell therapy vaccine to eliminate cells with latent HIV infection or cells present in viral sanctuaries. Due to the good results obtained in the exploratory stage of the project, the investigators propose to expand it by recruiting a larger number of patient to confirm the previously obtained results and to generate new insights related to the mechanisms involved in viral latency, latency disruption and the effects of analytical treatment interruption of antiretrovirals among patients undergoing all above mentioned interventions.

开始日期2025-04-01

申办/合作机构

Universidade Federal De Sao Paulo

[+1]

100 项与马拉韦罗相关的临床结果

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100 项与马拉韦罗相关的转化医学

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100 项与马拉韦罗相关的专利（医药）

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2,017

项与马拉韦罗相关的文献（医药）

2025-12-31·ASN Neuro

Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5

Article

作者: Vo, Phu ; Boakye-Agyei, Ama ; Nass, Sara R. ; Simons, Chloe A. ; Kim, Sarah ; Hahn, Yun K. ; Knapp, Pamela E. ; Hauser, Kurt F.

People living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND), even though combination antiretroviral therapy (cART) suppresses HIV replication. HIV-1 transactivator of transcription (HIV-1 Tat) contributes to the development of HAND through neuroinflammatory and neurotoxic mechanisms. C-C chemokine 5 receptor (CCR5) is important in immune cell targeting and is a co-receptor for HIV viral entry into CD4+ cells. Notably, CCR5 has been implicated in cognition unrelated to HIV infection. Inhibition of CCR5 has been shown to improve learning and memory. To test whether CCR5 is involved in cognitive changes in HAND, we used a non-infectious, transgenic model in which HIV-1 Tat is inducibly expressed. Well-powered cohorts of male and female mice were placed on a diet containing doxycycline to induce Tat expression for 8-wks. Males showed Tat-mediated deficits in the Barnes maze test of spatial learning and memory; females showed no impairments. Deficits in the males were fully reversed by the CCR5 antagonist, maraviroc (MVC). Tat-mediated deficits were not found in novel object recognition or contextual fear conditioning in either sex. Based on earlier work, we hypothesized that MVC might increase brain-derived neurotrophic factor (BDNF), which is essential in maintaining synaptodendritic function. MVC did increase the mBDNF to proBDNF ratio in males, perhaps contributing to improved cognition.

2025-07-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery and exploration of disubstituted [1,2,5]oxadiazolo-[3,4-b]pyrazines as novel C-C chemokine receptor type 5 signaling inhibitors targeting the intracellular allosteric binding pocket

Article

作者: Homer, Natalie Z M ; Verwilst, Peter ; Billen, Margaux ; Webster, Scott P ; Claes, Sandra ; Kaminski, Tim P ; Rozenski, Jef ; Bulai, Radu-George ; Reynders, Sten ; Schols, Dominique ; Lescrinier, Eveline ; Kleinboelting, Silke ; Rocca, Edoardo

The C-C chemokine receptor type 5 is a G protein-coupled receptor expressed on various immune cells, playing a crucial role in inflammation and chemotaxis. Beyond its physiological functions, C-C chemokine receptor type 5 is implicated in numerous diseases, including cardiovascular, central nervous system, immune system, and infectious diseases, as well as in the progression of cancer. The therapeutic potential of C-C chemokine receptor type 5 inhibition has been demonstrated by antagonists targeting the extracellular domain, notably maraviroc, a Food and Drug Administration-approved Human Immunodeficiency Virus entry inhibitor. However, challenges such as suboptimal pharmacokinetics and efficacy necessitate new antagonists with unique modes of action. Recent advancements in G protein-coupled receptor structural characterization have identified a novel intracellular allosteric binding site in chemokine receptors. This study introduces a series of disubstituted [1,2,5]oxadiazolo-[3,4-b]pyrazines targeting the intracellular allosteric binding pocket of C-C chemokine receptor type 5. Among these, compound 3ad emerged as a promising C-C chemokine receptor type 5-selective allosteric antagonist with a half-maximal inhibitory concentration of 1.09 μM and an almost 30-fold selectivity over C-C chemokine receptor type 2. Molecular dynamics simulations and a competition assay with a Gα_q11 mimetic were used to confirm the intracellular binding mode of these compounds. This novel class of C-C chemokine receptor type 5-selective intracellular antagonists offers a foundation for developing molecular tools and therapeutic agents, potentially overcoming the limitations of current extracellular C-C chemokine receptor type 5 antagonists.

2025-05-24·Journal of biomolecular structure & dynamics

Identification of approved drugs with ALDH1A1 inhibitory potential aimed at enhancing chemotherapy sensitivity in cancer cells: an in-silico drug repurposing approach

Article

作者: Paul, Sanjay Kumar ; Guendouzi, Abdelmadjid ; Banerjee, Agniswar ; Guendouzi, Abdelkrim ; Haldar, Rajen

The aldehyde dehydrogenase 1A1 (ALDH1A1) also known as retinal dehydrogenase, is an enzyme normally involved in the cellular metabolism, development and detoxification processes in healthy cells. However, it's also considered a cancer stem cell marker and its high levels of expression in several cancers, including breast, lung, ovarian, and colon cancer have been associated with poor prognosis and resistance to chemotherapy. Given its crucial role in chemotherapy resistance by detoxification of chemotherapeutic drugs, ALDH1A1 has attracted significant research interest as a potential therapeutic target for cancer. Though a few synthetic inhibitors of ALDH1A1 have been synthesized and their efficacy has been proved in-vitro and in-vivo studies, none of them have passed clinical trials so far. In this scenario, we have performed an in-silico study to verify whether any of the already approved drugs used for various purposes has the ability to inhibit catalytic activity of ALDH1A1, so that they can be repurposed for cancer therapy. Keeping in mind the feasibility of repurposing in a larger population we have selected the approved drugs from five widely used drug categories such as antibiotic, antiviral, antifungal, anti diabetic and antihypertensive for screening. Computational techniques like molecular docking, molecular dynamics simulations and MM-PBSA binding energy calculation have been used in this study to screen the approved drugs. Based on the logical analysis of results, we propose that three drugs - telmisartan, irbesartan and maraviroc can inhibit the catalytic activity of ALDH1A1 and thus can be repurposed to increase chemotherapy sensitivity in cancer cells.

项与马拉韦罗相关的新闻（医药）

2025-03-27

·小药说药

肿瘤免疫治疗中的趋化因子：解码微环境中的“导航信号”

-01- 引言趋化因子是负责免疫细胞运输和淋巴组织发育的细胞因子亚家族。目前，据报道有50种不同的趋化因子，根据其主要蛋白质结构的前两个半胱氨酸（C）残基的位置，可分为四大类，即C、CC、CXC和CX3C趋化因子。每个免疫细胞亚群都有不同的趋化因子受体表达模式，这使得它们对趋化因子有不同的反应，并根据每个环境的特殊需要迁移。在癌症中，它们在免疫细胞迁移到肿瘤中的模式中起着关键作用，从而形成肿瘤微环境的免疫特征，通常朝向促肿瘤形成状态。此外，趋化因子可以直接靶向肿瘤微环境中的非免疫细胞，包括肿瘤细胞、基质细胞和血管内皮细胞。因此，趋化因子参与多种癌症发展过程，如血管生成、转移、癌细胞增殖、干性和侵袭性，是疾病进展的关键决定因素，对患者预后和治疗反应有很大影响。由于它们在癌细胞和免疫浸润细胞中重要的调节功能，使得趋化因子配体及其受体成为非常强大的治疗靶点。 -02- 一、趋化因子在肿瘤免疫中的作用免疫逃避和免疫抑制细胞的募集趋化因子在引导免疫细胞迁移中起着至关重要的作用，而免疫细胞迁移是启动和传递有效的抗肿瘤免疫反应所必需的。TME中的趋化因子分泌通常会发生改变，异常的趋化因子分布可促进免疫抑制的促肿瘤细胞（即Treg细胞、MDSC和TAM）分化和浸润到肿瘤中。 Treg细胞的趋化因子受体CCR4的表达高于其他CD4+T细胞，其响应CCL22，一种由TAM和原发肿瘤细胞产生的趋化因子。除了CCR4外，Treg细胞还可以表达其他能够介导其浸润TME的趋化因子受体，如CCR5或CCR10，其配体CCL28存在于TME的缺氧区域。巨噬细胞主要通过CCL2–CCR2信号通路招募到TME中。CCL2的肿瘤表达与许多肿瘤中TAM的数量相关，并且通常与患者预后不良相关。与Treg细胞一样，TAM也可以抑制肿瘤相关抗原（TAA）特异性CD8+T细胞活化。与TAM非常相似，髓源性抑制细胞（MDSC）也可以通过CCL2–CCR2信号被招募到TEM中。此外，诱导单核细胞向肿瘤募集的其他趋化因子还有CCL5、CCL7、CCL15、CXCL8和CXCL12。浆细胞样树突状细胞（pDC）是一种罕见的免疫细胞，也能抑制抗肿瘤免疫反应。肿瘤和基质细胞产生CXCL12，它是趋化因子受体CXCR4的配体，由pDCs表达。因此，CXCL12是pDC进入TME的关键分子。此外，CXCL12还对pDC发挥保护作用，防止其发生凋亡，延长其免疫抑制作用。肿瘤生长与进展一些研究表明，趋化因子信号系统通过不同的机制参与肿瘤生长和进展。癌细胞表达的趋化因子受体与肿瘤相关成纤维细胞、肿瘤细胞和TME浸润性免疫细胞分泌的各自配体之间的相互作用可直接激活PI3K/AKT和ERK 1/2等信号通路，导致癌细胞增殖。肿瘤细胞上趋化因子受体的病理性过度表达和TME中趋化因子配体的分泌可加剧这些效应。此外，趋化因子可以通过在肿瘤细胞中产生促凋亡和抗凋亡蛋白之间的失衡，例如下调Bcl-2表达或抑制caspase-3和caspase-9激活来维持癌细胞存活，从而避免肿瘤细胞凋亡。某些免疫细胞的趋化因子募集也有助于肿瘤的发生。分泌IL-22的T辅助细胞（TH22）是TME中常见的免疫细胞亚群，已被证明通过多种途径支持肿瘤发生，特别是在结肠癌中。它们表达趋化因子受体CCR6，并向TME中存在的配体CCL20迁移，在那里它们能够通过细胞因子表达增加肿瘤细胞的干性和致瘤潜能。血管生成趋化因子及其各自的受体被认为是肿瘤血管系统的关键调节因子，在肿瘤血管生成中具有双重作用。根据N端是否存在ELR（Glu-Leu-Arg）基序，CXC趋化因子可分为两类：ELR+趋化因子和ELR−趋化因子。通过激活CXCR1和CXCR2发挥作用的ELR+CXC趋化因子，包括CXCL1、CXCL2、CXCL3、CXCL5、CXCL6、CXCL7和CXCL8，具有血管生成作用。相反，ELR−CXC趋化因子，如CXCL4、CXCL9、CXCL10、CXCL11和CXCL14被认为是血管生成抑制剂。趋化因子可以通过直接与内皮细胞上的趋化因子受体相互作用作为肿瘤血管生成介质，从而改善迁移和增殖以及内皮细胞存活。此外，趋化因子还可能通过促进TME中产生血管生成因子的白细胞的募集间接发挥作用，从而增强血管生成。趋化因子还可以与其他血管生成促进剂协同作用，如血管内皮生长因子（VEGF）。另一方面，趋化因子还具有抑制肿瘤血管生成和内皮细胞增殖的活性。例如，CXCL4和CXCL10是具有血管抑制特性的趋化因子，包括抑制由成纤维细胞生长因子和VEGF诱导的血管生成以及阻止内皮细胞趋化性和增殖。此外，CXCL9、CXCL10和CXCL11与表达CXCR3的免疫细胞的相互作用可能招募具有血管抑制功能的细胞。促进转移大量研究证实了趋化因子系统在肿瘤转移中的关键作用。据报道，癌细胞上的趋化因子受体表达可以确定其转移的部位。这些转移部位产生的特异性趋化因子可以促进循环癌细胞迁移到“转移前生态位”，这为转移细胞的生长提供了有利的环境。多种趋化因子和趋化因子受体与转移有关，CXCL12/CXCR4轴代表了这一现象的关键因素，在不同的肿瘤中已证实其参与肿瘤转移。参与癌症转移的其他趋化因子的例子有CCR7，它通过与转移部位分泌的CCL19和CCL21配体相互作用，介导癌细胞向淋巴器官的迁移；CCL28是CCR3/CCR10的配体，与乳腺癌生长和转移扩散相关；CCR10/CCL27信号支持转移扩散期间黑色素瘤细胞的粘附和存活，CXCR5/CXCL13相互作用似乎支持前列腺癌的骨转移。 -03- 二、趋化因子的靶向治疗目前，临床已批准的靶向趋化因子的药物包括：抗CCR4抗体（Mogamulizumab）和CXCR4拮抗剂（Plerixafor，AMD3100），用于血液恶性肿瘤。此外，还有更多的针对不同趋化因子受体-配体轴作为癌症治疗策略的多种努力，这些治疗策略目前已表现出巨大的潜力，正处于临床开发中。 CCR1 CCR1在几种类型的癌症中过表达，并与免疫抑制细胞浸润和转移增加有关。以CCR1为靶点的大多数治疗益处来源于减少MDSC浸润，最终抑制肿瘤生长和转移。选择性CCR1拮抗剂CCX721能够通过阻断破骨细胞减少多发性骨髓瘤（MM）骨病小鼠模型中的肿瘤负担和溶骨性病变。另一项研究报告称，使用受体拮抗剂BL5923抑制CCR1可抑制未成熟髓样细胞的募集，减少转移性结肠癌，显著延长结肠癌肝转移小鼠的生存期。CCR1拮抗剂CCX9588与抗PD-L1抗体的组合已被证明是一种很有前途的治疗方法，因为它通过抑制原位乳腺癌小鼠模型中的原发肿瘤生长和肺转移产生协同抗肿瘤作用。最近，在卵巢癌的小鼠模型中，小分子CCR1抑制剂UCB35625也能够减少细胞向大网膜的迁移，而大网膜是此类癌症的优先转移部位。总的来说，这些结果表明，以CCR1为靶点是一种可行的治疗策略，可以限制转移并延缓疾病进展。 CCR2，CCL2 已证明CCL2/CCR2轴能够将免疫抑制细胞（如MDSC和促进转移的单核细胞）招募到TME中，阻断CCL2/CCR2轴已在几种恶性肿瘤中显示出抗肿瘤作用。一些研究集中于CCR2抑制剂对胰腺癌的治疗，使用口服CCR2抑制剂PF-04136309，通过在体内小鼠模型中抑制CCR2信号来靶向TAM，可提高化疗疗效、阻断转移和增加抗肿瘤T细胞反应。在转移性胰腺导管腺癌的Ib/II期试验（NCT02732938）中，该分子与Abraxane（nab紫杉醇）和吉西他滨联合使用获得了良好的结果。另一项II期临床试验评估了CCR2抑制剂与常规化疗方案FOLFIRINOX（FX）联合应用于边缘可切除或局部晚期胰腺导管腺癌患者，证实了该疗法的安全性和耐受性。值得注意的是，使用小分子CCX872抑制CCR2提高了在胰腺癌小鼠模型中抗PD-1/ PD-L1免疫疗法的治疗效果。另一项评估CCR2拮抗剂RDC018对肝细胞癌的临床前研究显示，其抑制了肿瘤生长和转移，减少了术后复发，延长了生存期。 CCL2是受体CCR2的主要配体，阻断CCL2通过增强放疗的效果和预防转移在临床前研究中显示出抗肿瘤活性。然而，抗CCL2的单抗carlumab（CNTO 888）在实体瘤（NCT00992186）和转移性前列腺癌（NCT00537368）的1期和2期临床试验中，由于其无法降低CCL2血清水平，未能证明临床益处。 CCR4 CCR4除了是调节性T细胞的主要趋化因子受体，还在几种T细胞恶性肿瘤中过表达。抗CCR4抗体Mogamulizumab最初用于治疗难治性霍奇金淋巴瘤，目前在日本用于治疗复发性成人T细胞白血病，并在皮肤T细胞淋巴瘤的III期临床试验中成功提高了无进展生存率和生活质量。 Mogamulizumab是一种人源化单克隆抗体，具有一个去岩藻糖基化的Fc区域，以增强效应细胞结合，能够通过抗体依赖性细胞毒性（ADCC）诱导恶性T细胞消除。两项独立临床试验表明，Mogamulizumab可单独或与抗PD-1抗体Nivolumab联合安全用于晚期或转移性实体瘤的治疗。目前，还有一些其他的CCR4疗法正在开发中，包括抗CCR4 CAR-T细胞，已证明其对几种T细胞恶性肿瘤有效，以及小分子CCR4拮抗剂，能够通过防止Treg诱导提高抗癌疫苗的效力。 CCR5 抗CCR5的人源化单克隆抗体leronlimab和小分子CCR5抑制剂maraviroc和vicriviroc在几种恶性肿瘤中均显示出有希望的结果。这三种药物均能阻断免疫缺陷小鼠体内人乳腺癌异种移植物的转移，并能增强DNA损伤化疗药物对细胞的杀伤作用。Maraviroc和vicriviroc还能够在前列腺癌小鼠模型中减少全身、骨骼和大脑中的细胞转移，而Maraviroc在结直肠癌模型中限制癌相关成纤维细胞的聚集，导致肿瘤生长减少。此外，maraviroc在一项临床试验（MARACON）中显示了有希望的结果，该试验降低了对标准化疗无效的结直肠癌患者的肿瘤细胞生长，而另外两项临床试验分别评估了Pembrolizumab与maraviroc或Vicriviroc对难治性微卫星稳定结直肠癌的联合抑制作用，结果显示，延长了疾病稳定时间，生存率高于预期。目前正在对CCR5+转移性癌症患者进行其他临床试验，以评估CCR5拮抗剂与其它药物的组合。 CCR7 CCR7中和疗法在许多临床前模型中显示了有希望的结果。在前列腺癌、乳腺癌和结直肠癌模型中，通过siRNA或miRNA沉默CCR7基因表达导致转移和肿瘤生长减少。抗CCR7单克隆抗体在T细胞淋巴细胞白血病异种移植小鼠模型中显示出诱导肿瘤细胞死亡，并减少或避免中枢神经系统疾病的能力，而单链抗CCR7抗体在体外模型中成功阻止T细胞急性淋巴细胞白血病细胞通过血脑屏障。 CXCR2 CXCR2–CXCLs轴是一个重要的趋化因子，CXCR2–CXCLs轴促进肿瘤进展的机制很多，但最显著的是与中性粒细胞募集到TME和促进血管生成有关。 CXCR2的中和在各种临床前癌症模型中显示出了有希望的结果，通常作为联合治疗的一部分来规避化疗耐药性。在黑色素瘤模型中，CXCR2抑制剂Navarixin与MAPK抑制具有协同作用，而抑制剂SB225002改善了卵巢肿瘤模型中索拉非尼的抗血管生成治疗。CXCR1和CXCR2抑制剂Reparixin与5-氟尿嘧啶联合使用时，也能够改善胃癌模型中的肿瘤细胞凋亡并减少肿瘤体积。AZ13381758是一种CXCR2的小分子抑制剂，与吉西他滨联合使用时，能够减少胰腺导管腺癌模型的转移并显著延长寿命。目前，七种CXCR2抑制剂正在多项临床试验中进行研究，其中四种用于治疗转移性恶性肿瘤。其中包括用于治疗前列腺癌（2期）、头颈部鳞状细胞癌（1b/2期）和胰腺导管癌（1b/2期）的AZD5069/AZD9150；Reparixin用于治疗乳腺癌（2期）；Navarixin用于治疗前列腺癌和非小细胞癌（2期）；SX-682用于治疗III期和IV期黑色素瘤（1期）。 CXCR4 鉴于CXCR4与多种恶性肿瘤的生长和扩散具有无可争议的临床相关性，在过去十年中，已经开发出许多CXCR4靶向的肽和非肽拮抗剂。 CXCR4拮抗剂，如AMD3100和AMD3465，通过介导来自骨髓环境的肿瘤细胞的转运，增强了传统疗法的临床疗效。复发性AML患者的I/II期研究（NCT00512252）提供的数据显示，CXCR4/CXCL12轴阻断的体内疗效与令人鼓舞的缓解率之间的相关性。人源化CXCR4抗体PF-06747143在包括NHL、AML和MM在内的多种血液肿瘤模型中显示出强烈的抗肿瘤作用。在急性髓系淋巴瘤患者中进行了一项I期试验（NCT02954653），评估其安全性和耐受性，但由于主办方的原因，该试验不幸终止。最近，另一种抗CXCR4抗体ulocuplumab（BMS-936564）的Ib/II期试验（NCT01359657）证实，阻断CXCR4–CXCL12轴是安全的，并且与来那度胺和地塞米松联合治疗复发性/难治性骨髓瘤患者具有较高的应答率。 CXCR4抑制剂在实体瘤中也被证明具有重要的抗癌潜力。目前有几项临床试验正在评估CXCR4拮抗剂对胶质母细胞瘤患者的临床益处。一项I/II期试验（NCT01977677）研究了plerixafor在替莫唑胺和放射治疗后的副作用和最佳剂量，结果显示，plerixafor未观察到剂量限制性毒性，并且似乎在RT后抑制CXCL4介导的血管生成，增强了放射治疗的效果。除脑肿瘤外，AMD3465还能够预防体内乳腺癌生长和转移，而新型环肽CXCR4拮抗剂LY2510924在各种实体瘤和转移性乳腺癌临床前模型中显示出抗肿瘤活性。LY2510924在一期试验（NCT02737072）中进行试验，耐受性良好。对于HER2阴性转移性乳腺癌患者，CXCR4拮抗剂balixafortide作为单一疗法以及与其他药物联合使用的I期试验（NCT01837095）取得了有希望的初步结果。值得注意的是，CXCR4抑制也被证明能促进强烈的抗肿瘤T细胞反应。卵巢癌临床前模型中的CXCR4阻断能显著增加T细胞介导的抗肿瘤免疫反应，使AMD3100治疗的小鼠具有显著的生存优势。BPRCX807是一种选择性和有效的CXCR4拮抗剂，最近在肝细胞癌小鼠模型的体外和体内试验中显示了良好的效果。 -04- 结语趋化因子是一大类协调免疫细胞运输的趋向性的细胞因子。鉴于趋化因子在肿瘤免疫反应和肿瘤生物学中发挥着的多方面作用，趋化因子网络已成为潜在的免疫治疗靶点。趋化因子受体及其配体之间存在非常复杂的相互作用，为了引入新一代基于趋化因子调节的免疫肿瘤治疗策略，迫切需要深入了解肿瘤微环境生物学以及更好的预测性临床模型。尽管面临挑战，大量针对不同趋化因子信号通路的趋化因子受体抑制剂目前正在临床前研究和临床试验中进行评估，并且与常规化疗或免疫检查点疗法结合使用时，显示出有希望的结果。因此，可以预测，在不久的将来，趋化因子受体抑制剂将用于调节TME的组成并优化患者的免疫反应，为肿瘤患者带来希望。参考资料： 1.Chemokine-Directed Tumor MicroenvironmentModulation in Cancer Immunotherapy. Int J Mol Sci. 2021 Sep; 22(18): 9804. 公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

免疫疗法

2025-02-10

·GlobeNewswire-Health Care

Tonix Pharmaceuticals Announces Acquisition of Preclinical Infectious Disease Portfolio from Healion Bio, Inc.

The Acquired Portfolio of Infectious Disease Assets Includes a Class of Potential Broad Spectrum Oral Antiviral Agents, TNX-3900 with a Host-Directed Mechanism Tonix Plans to Develop the TNX-3900 Series of Molecules as Oral Antivirals Either as Monotherapy or in Combination with Other Antivirals The TNX-3900 Class of Antivirals Has a Novel Mechanism of Action Based on Inhibition of Certain Cathepsin Proteases which are Required for Cell Infection by Many Viruses like SARS-CoV-2 Sina Bavari, Ph.D., Tonix EVP of Infectious Disease R&D and Director of the Frederick, MD Research and Development Center (RDC) was a Scientific Founder of Healion Bio, Inc. Feb. 02, 2023 -- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced an agreement whereby Tonix has acquired all of the assets of Healion Bio, Inc. (Healion) including its entire portfolio of next-generation antiviral technology assets. Healion’s drug portfolio includes a class of broad-spectrum small molecule oral antiviral drug candidates with a novel host-directed mechanism of action. Host-directed antivirals modulate human cells and tissues and are different from direct-acting antivirals which inhibit virus proteins and processes. Tonix’s TNX-3900, formerly known as HB-121, are cathepsin protease inhibitors, some of which have strong activity in vitro against SARS-CoV-2. “We are excited to develop Healion’s drug programs that include TNX-3900, which is a class of drugs with potential broad spectrum anti-viral activity, either as monotherapies or in combination with other antivirals”, said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. “Broad-spectrum antiviral agents have the potential to reduce viral load and allow the adaptive immune system to alert the other arms of the immune system to mount a protective response. Examples of other classes of host-directed antivirals that have been approved by the U.S. Food and Drug Administration (FDA) include alpha interferon like Pegasys® (peginterferon alfa-2a) for viral hepatitis, the CCR5 antagonist Selzentry® (maraviroc) for HIV, and the anti-IL-6 receptor antagonist monoclonal antibody Actemra® (tocilizumab) for COVID-19.” Sina Bavari, Ph.D., Executive Vice President for Infectious Disease Research at Tonix said, “I am pleased to be reunited with the infectious disease assets of Healion, since I was the scientific founder of Healion after I retired from my position as Chief of R&D at the United States Army Medical Research Institute of Infectious Disease (USAMRIID). While Healion made some progress developing these advanced technologies, Tonix’s state-of-the art facilities and depth of drug development expertise have the potential to advance the TNX-3900 class of drugs into clinical trials. On behalf of the talented scientific team that I direct at our 48,000 square-foot cutting-edge infectious disease research facility in Frederick, Md., I am pleased to add this technology to the therapeutic development programs underway.” TNX-3900 is the term for a series of molecules that inhibit essential cathepsins which are required by viruses such as coronaviruses and filoviruses to infect cells. Because of the unique antiviral mechanism of these compounds, the Company believes they can potentiate the activity of other antivirals with differing mechanisms. The Company believes this makes cathepsin inhibitors suitable for combination therapy. Tonix is a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics to treat and prevent human disease and alleviate suffering. Tonix’s portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious disease product candidates. Tonix’s CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s lead CNS candidate, TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is in mid-Phase 3 development for the management of fibromyalgia with a new Phase 3 study launched in the second quarter of 2022 and interim data expected in the second quarter of 2023. TNX-102 SL is also being developed to treat Long COVID, a chronic post-acute COVID-19 condition. Tonix initiated a Phase 2 study in Long COVID in the third quarter of 2022. TNX-1300 (cocaine esterase) is a biologic designed to treat cocaine intoxication and has been granted Breakthrough Therapy designation by the FDA. A Phase 2 study of TNX-1300 is expected to be initiated in the second quarter of 2023. TNX-1900 (intranasal potentiated oxytocin), a small molecule in development for chronic migraine, is expected to enter the clinic with a Phase 2 study in the first quarter of 2023. TNX-601 ER (tianeptine hemioxalate extended-release tablets) is a once-daily formulation of tianeptine being developed as a potential treatment for major depressive disorder (MDD) with a Phase 2 study expected to be initiated in the first quarter of 2023. Tonix’s rare disease portfolio includes TNX-2900 (intranasal potentiated oxytocin) for the treatment of Prader-Willi syndrome. TNX-2900 has been granted Orphan Drug designation by the FDA. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmunity and cancer, including TNX-1500, which is a humanized monoclonal antibody targeting CD40-ligand (CD40L or CD154) being developed for the prevention of allograft and xenograft rejection and for the treatment of autoimmune diseases. A Phase 1 study of TNX-1500 is expected to be initiated in the second quarter of 2023. Tonix’s infectious disease pipeline includes a vaccine in development to prevent smallpox and monkeypox, TNX-801, a next-generation vaccine to prevent COVID-19, TNX-1850, a platform to make fully human monoclonal antibodies to treat COVID-19, TNX-3600, and humanized anti-SARS-CoV-2 monoclonal antibodies, TNX-3800, recently licensed from Curia. TNX-801, Tonix’s vaccine in development to prevent smallpox and monkeypox, also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases. A Phase 1 study of TNX-801 is expected to be initiated in Kenya in the second half of 2023. The content above comes from the network. if any infringement, please contact us to modify.

疫苗突破性疗法免疫疗法孤儿药

2025-02-03

·漫游药化

突破！羧酸也可以做还原胺化反应

在有机合成中，C-N键的构建非常常见，方法也有很多，像取代反应，Buchwald偶联反应等等。另外一个不得不提的方法当属还原胺化了，做合成的同学和朋友们应该很少有没做过这类反应的，醛酮与胺在还原剂如硼氢化钠，氰基硼氢化钠，三乙酰基硼氢化钠等的参与下得到饱和的碳氮键。对于活性较低的底物有时候需要预制备亚胺，如四异丙氧基钛的参与。羰基类化合物特别是醛有时候往往不稳定，它的伙伴羧酸就稳定多了。今天，小编和大家分享一篇高分期刊Chemical Science（RSC旗下期刊）报道的英国诺丁汉大学和制药巨头GSK（葛兰素史克）合作报道的催化羧酸还原胺化反应，突破传统的醛与胺的还原胺化反应（Chem. Sci., 2020, 11, 9494）。在这里小编先讲应用，对应用D，也就是红色圈起来的印象非常深刻，极大缩短Pfizer开发的药物maraviroc的工艺路线，产率有明显提高。我们再来看看反应的底物普适性，从下图可以看出不管是脂肪酸，芳香酸，还是脂肪一级胺，二级胺，还是芳胺都能很好地进行反应，以良好到优秀的产率得到目标产物。在这个反应中苯硅烷即作为媒介参与第一步的酰胺形成反应，又参与醋酸锌催化的第二步的酰胺还原反应。在这个反应过程中，稍过量的羧酸起到至关重要的角色，活化苯硅烷，增加还原能力。本文报道的羧酸还原胺化方法对药物研发人员来说绝对是一个福利，可以极大地提高药物Discovery阶段的研发速度。参考文献： Chem. Sci., 2020,11, 9494-9500

临床研究

100 项与马拉韦罗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06670	马拉韦罗	J05AX09	DB04835

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
HIV感染	美国	ViiV Healthcare Co.	2007-08-06

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脂肪肝	临床3期	英国	ViiV Healthcare Ltd.	2017-03-01
代谢功能障碍相关的脂肪肝病	临床3期	英国	ViiV Healthcare Ltd.	2017-03-01
非酒精性脂肪肝	临床3期	英国	ViiV Healthcare Ltd.	2017-03-01
艾滋病痴呆复合征	临床3期	美国	ViiV Healthcare Ltd.	2015-06-01
艾滋病痴呆复合征	临床3期	波多黎各	ViiV Healthcare Ltd.	2015-06-01
心血管疾病	临床3期	美国	Pfizer Inc.	2010-01-01
炎症	临床3期	美国	Pfizer Inc.	2010-01-01
获得性免疫缺陷综合征	临床3期	巴西	Pfizer Inc.	2007-07-01
获得性免疫缺陷综合征	临床3期	巴西	ViiV Healthcare Ltd.	2007-07-01
新型冠状病毒感染	临床2期	西班牙	ViiV Healthcare Ltd.	2020-06-26

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05932550 (Pubmed)	临床2期	抑郁症追加 CCR5	10	Maraviroc 300 mg	齋鹽襯選鬱製廠淵獵鏇(窪網鹹艱築簾築選壓願) = 窪積夢醖遞齋淵鏇顧選顧蓋鬱鹹淵製夢遞窪鬱 (簾夢齋鏇遞膚鑰範遞憲, 9.3)	积极	2024-06-06
NCT02881762 (MAVERIC, CTgov)	临床4期	HIV感染 \| 丙型肝炎	10	Maraviroc (Maraviroc)	鹹憲網鏇鏇構齋鹽鑰糧(窪鏇夢糧簾願廠糧鑰願) = 鑰餘衊顧遞構鹽鏇網衊窪築觸積襯觸壓鹹遞積 (遞糧艱製獵膚壓製範鏇, 1012880) 更多	-	2024-05-01
NCT02881762 (MAVERIC, CTgov)	临床4期	HIV感染 \| 丙型肝炎	10	Maraviroc (No Maraviroc)	鹹憲網鏇鏇構齋鹽鑰糧(窪鏇夢糧簾願廠糧鑰願) = 遞襯鹽繭夢壓築觸淵簾窪築觸積襯觸壓鹹遞積 (遞糧艱製獵膚壓製範鏇, 1411027) 更多	-	2024-05-01
NCT04435522 (CTgov)	临床1期	新型冠状病毒感染	9	maraviroc	鑰獵築蓋遞鏇願糧鑰獵 = 簾窪繭獵簾廠製願築齋選衊獵鑰網觸簾鏇蓋製 (齋膚壓艱獵鑰選積築壓, 鹽觸築蓋積艱遞廠積襯 ~ 襯築壓衊構鹹鹽壓衊鹹) 更多	-	2024-04-29
NCT02741323 (CTgov)	临床2期	肾脏疾病 \| HIV感染	97	maraviroc (Arm 1: Maraviroc (MVC))	壓繭鏇壓窪鬱艱願獵淵(願齋齋艱夢醖廠積築窪) = 壓網鑰鏇範築獵艱糧夢鏇膚醖淵獵遞衊淵構觸 (積衊壓壓製壓遞淵鹹餘, 鏇蓋鹽築糧鹽簾網願繭 ~ 獵選蓋選鬱夢糧膚壓鬱) 更多	-	2023-08-21
NCT02741323 (CTgov)	临床2期	肾脏疾病 \| HIV感染	97	Placebo (Arm 2: Placebo)	壓繭鏇壓窪鬱艱願獵淵(願齋齋艱夢醖廠積築窪) = 願齋願壓網齋鹽鬱艱醖鏇膚醖淵獵遞衊淵構觸 (積衊壓壓製壓遞淵鹹餘, 膚糧繭夢襯範蓋醖願築 ~ 鬱壓構繭膚顧衊蓋蓋築) 更多	-	2023-08-21
S20.004 (AAN2023)	N/A	抑郁症 natural-occurring mutation that blocks CCR5	10	Maraviroc 300mg/day	繭憲憲遞繭艱鹽淵膚蓋(遞鬱餘淵鬱遞繭淵網餘) = Maraviroc was well tolerated with no reported adverse events or discontinuation due to intolerance 範壓醖積鹹願糧構簾窪 (衊願遞繭廠遞選積獵艱 ) 更多	积极	2023-04-25
NCT02519777 (CTgov)	临床4期	认知功能障碍 \| HIV感染	191	Placebo for dolutegravir (DTG) (Arm A: Placebo MVC and Placebo DTG)	製齋鏇艱鹹淵範鬱窪網(積遞醖鬱鑰夢夢範顧醖) = 選糧獵鹹糧夢築鏇鑰願蓋糧醖鑰構獵壓壓襯衊 (膚顧餘繭製遞鬱艱網顧, 鹹壓鹹憲壓鹹獵廠齋淵 ~ 鹽鬱鏇齋窪遞觸蓋鑰壓) 更多	-	2022-03-02
NCT02519777 (CTgov)	临床4期	认知功能障碍 \| HIV感染	191	Placebo for maraviroc (MVC)+Dolutegravir (DTG) (Arm B: DTG and Placebo MVC)	製齋鏇艱鹹淵範鬱窪網(積遞醖鬱鑰夢夢範顧醖) = 廠顧製襯鬱艱窪製觸艱蓋糧醖鑰構獵壓壓襯衊 (膚顧餘繭製遞鬱艱網顧, 範鬱壓製選齋製積簾顧 ~ 遞遞網獵鑰鏇襯鏇願網) 更多	-	2022-03-02
NCT03172026 (MAROS, CTgov)	临床2/3期	脑卒中	2	Rehabilitation therapy+Maraviroc 300 mg (Maraviroc + Augmented Rehabilitation)	壓網顧範餘製齋願獵顧(鹹蓋蓋網製鹹獵顧餘鏇) = 壓顧遞糧蓋夢夢膚醖艱選淵憲顧顧夢窪淵憲齋 (憲醖鏇蓋積獵觸糧簾糧, 糧襯鑰製壓膚選夢鬱夢 ~ 夢繭鹹願壓壓襯憲願淵) 更多	-	2021-08-03
NCT03172026 (MAROS, CTgov)	临床2/3期	脑卒中	2	Placebo 300 mg (Placebo + Augmented Rehabilitation)	壓網顧範餘製齋願獵顧(鹹蓋蓋網製鹹獵顧餘鏇) = 鏇範網範齋壓衊簾範餘選淵憲顧顧夢窪淵憲齋 (憲醖鏇蓋積獵觸糧簾糧, 構醖遞遞憲壓憲繭醖襯 ~ 鬱築繭鬱構餘鹽築淵網) 更多	-	2021-08-03
NCT03274804 (PICCASSO, CTgov)	临床1期	脊髓小脑变性 \| 转移性微卫星稳定结直肠癌 \| 转移性结直肠癌	20	pembrolizumab+maraviroc	餘壓醖襯糧壓蓋鏇夢膚 = 觸鏇構鏇顧淵醖憲醖餘簾願鹽蓋膚窪網簾獵遞 (範顧鹽齋積鏇廠鬱鏇憲, 簾願憲製築簾鬱鹽齋鬱 ~ 鏇齋鑰積餘醖淵繭衊鏇) 更多	-	2021-04-22
NCT01276236 (CTgov)	临床2期	艾滋病相关性卡波西肉瘤	13	maraviroc	衊獵網憲鏇廠構廠窪鏇 = 淵構繭繭壓積鏇網願膚遞鏇淵蓋壓淵繭餘齋壓 (膚艱齋艱襯選鏇齋艱憲, 襯觸觸選淵鏇廠顧壓鏇 ~ 獵繭積築遞餘鑰蓋襯簾) 更多	-	2021-03-05
NCT01785810 (CTgov)	临床2期	急性髓性白血病 \| 慢性淋巴细胞白血病 \| 急性淋巴细胞白血病 ... 更多	37	Maraviroc 300 mg	鹽顧觸衊繭窪鑰淵鹹鏇 = 顧衊鹽鬱膚繭顧獵壓糧選廠築糧繭構廠積襯顧 (淵選製願遞網餘獵顧醖, 艱醖憲選積蓋簾餘範淵 ~ 艱選鹽鑰築範膚願蓋窪) 更多	-	2021-01-11