Development of PTLS-209 for treatment for giardiasis

开发用于治疗贾第鞭毛虫病的 PTLS-209

基本信息

  • 批准号:
    10849944
  • 负责人:
  • 金额:
    $ 63.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-12 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary: This project focuses on the development of treatment to combat giardiasis resistance to standard care drugs. Giardia lamblia is a highly infective waterborne parasite that causes severe diarrhea. Current antigiardiasis drugs fail in about 20% of cases, and they all have undesirable side effects. Additionally, drug-resistant G. lamblia strains can be readily raised in the laboratory, increasing the risk of this category B bioterrorism organism. Chronic infection of giardiasis and lack of treatment in developing countries lead to malnutrition, growth retardation in children, and death. Thus, the prevalence of giardiasis impacts global health profoundly, and the World Health Organization has included giardiasis in its Neglected Diseases Initiative. Our collaborators and NCATS/NIH investigators identified fumagillin as a lead compound through screening an approved drug library. Fumagillin kills Giardia trophozoites in vitro with high potency via MetAP2 inhibition. It has also shown excellent efficacy in an in vivo mouse model; however, it has two liabilities: heat and humidity instability, as well as potential toxicity in humans. These liabilities hamper the further development of fumagillin. We addressed these issues during our lead optimization process and identified PTLS-209, which has high potency for MetAP2, low bioavailability, improved efficacy, and enhanced stability. Thus, PTLS-209 has the ideal attributes to be an effective and safe intestinal targeting drug for treating giardiasis, particularly drug-resistant giardiasis. The arsenal of drugs available for treating giardiasis belongs to only a few chemical classes, primarily nitroimidazoles, thiazolides, and benzimidazoles. G. lamblia drug resistance already exists for each of these classes of compounds. None of the currently used drugs to treat giardiasis act on the MetAP2 enzyme. Thus, PTLS-209, a fumagillin analog, will not be subject to the current drug resistance mechanisms that result in treatment failures. PTLS-209 has an excellent safety profile, while other analogs of the fumagillin class, beloranib, ZGN-1061, and ZGN-1258, have shown adverse effects in preclinical studies and clinical trials. Note that these analogs were administered subcutaneously, whereas PTLS-209 is administered orally and has a very low oral bioavailability in mice (which may be the cause of its low toxicity). In order to mitigate the risks early, we have adopted the “Fail Early, Fail Cheap” approach. We propose two critical tests to evaluate these toxicity concerns in our SBIR Phase I portion of the Fast-Track application. Once we meet our Phase I milestones, we will continue IND-enabling studies to ensure that PTLS-209 has all the attributes to be a successful treatment for giardiasis and will file an IND application.
项目概要: 该项目的重点是开发治疗方法,以消除贾第虫病对标准治疗药物的耐药性。 贾第虫是一种高传染性的水传播寄生虫,可引起严重的腹泻。目前的抗贾第虫病药物 大约有20%的病例失败,而且它们都有不良的副作用。此外,耐药G.蓝氏 这些菌株很容易在实验室中培养,增加了这种B类生物恐怖主义微生物的风险。 发展中国家贾第鞭毛虫病的慢性感染和缺乏治疗导致营养不良和生长发育 儿童发育迟缓和死亡。因此,贾第鞭毛虫病的流行深刻地影响着全球健康, 世界卫生组织已将贾第虫病列入其被忽视疾病倡议。 我们的合作者和NCATS/NIH的研究人员通过筛选一种新的化合物, 批准的药物库。烟曲霉素通过MetAP 2抑制作用在体外高效杀死贾第鞭毛虫滋养体。它有 在体内小鼠模型中也显示出优异的功效;然而,它有两个缺点:热和湿度 不稳定性以及对人体的潜在毒性。这些不利因素阻碍了烟曲霉素的进一步发展。 我们在铅优化过程中解决了这些问题,并确定了PTLS-209, MetAP 2的效力、低生物利用度、改善的功效和增强的稳定性。因此,PTLS-209具有理想的 是一种有效、安全的肠靶向治疗贾第鞭毛虫病,特别是耐药贾第鞭毛虫病的药物, 贾第虫病 可用于治疗贾第虫病的药物库仅属于少数化学类别,主要是 硝基咪唑、噻唑和苯并咪唑。G.这些细菌中的每一种都已经存在蓝氏杆菌耐药性 化合物的种类。目前使用的治疗贾第虫病的药物都不作用于MetAP 2酶。因此,在本发明中, PTLS-209是一种烟曲霉素类似物,不会受到目前的耐药机制的影响, 治疗失败。 PTLS-209具有优异的安全性特征,而烟曲霉素类的其他类似物贝洛拉尼、ZGN-1061和ZGN-1062具有优异的安全性特征。 ZGN-1258在临床前研究和临床试验中显示出不良反应。注意,这些类似物是 PTLS-209是皮下给药,而PTLS-209是口服给药,口服生物利用度非常低 在小鼠中(这可能是其低毒性的原因)。为了尽早降低风险,我们采用了“失败 早期,失败便宜"的方法。我们提出了两个关键的测试,以评估这些毒性问题,在我们的SBIR阶段 快速通道申请的一部分。一旦我们达到第一阶段的里程碑,我们将继续推动IND 研究,以确保PTLS-209具有成功治疗贾第虫病的所有属性,并将提交一份 IND申请。

项目成果

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Janak K Padia其他文献

Janak K Padia的其他文献

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{{ truncateString('Janak K Padia', 18)}}的其他基金

Development of PTLS-209 for treatment for giardiasis
开发用于治疗贾第鞭毛虫病的 PTLS-209
  • 批准号:
    10483491
  • 财政年份:
    2022
  • 资助金额:
    $ 63.4万
  • 项目类别:
Development of an adenosine A1 receptors agonist, MRS5474 for the treatment of chronic depression
开发用于治疗慢性抑郁症的腺苷 A1 受体激动剂 MRS5474
  • 批准号:
    10220705
  • 财政年份:
    2018
  • 资助金额:
    $ 63.4万
  • 项目类别:
Development of an adenosine A1 receptors agonist, MRS5474 for the treatment of chronic depression
开发用于治疗慢性抑郁症的腺苷 A1 受体激动剂 MRS5474
  • 批准号:
    9797678
  • 财政年份:
    2018
  • 资助金额:
    $ 63.4万
  • 项目类别:

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Development of PTLS-209 for treatment for giardiasis
开发用于治疗贾第鞭毛虫病的 PTLS-209
  • 批准号:
    10483491
  • 财政年份:
    2022
  • 资助金额:
    $ 63.4万
  • 项目类别:
Sub-micron superconducting PTLs for SFQ logic circuits
用于SFQ逻辑电路的亚微米超导PTL
  • 批准号:
    18080002
  • 财政年份:
    2006
  • 资助金额:
    $ 63.4万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
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