Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
基本信息
- 批准号:8860114
- 负责人:
- 金额:$ 69.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-04 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAminoglycosidesAnti-Bacterial AgentsAntibioticsBacterial InfectionsBacterial ProteinsBindingBiochemicalBiological AssayBiological FactorsCellsChemicalsClinicalClinical TrialsComputer AssistedDataDevelopmentDrug DesignDrug KineticsDrug resistanceEnsureEnzymesEvaluationFutureFuture GenerationsGenerationsHealthIn VitroInfectionLeadMedicalModificationMolecular WeightMulti-Drug ResistanceNational Institute of Allergy and Infectious DiseaseNeisseria gonorrhoeaeOrganismPharmaceutical PreparationsPositioning AttributePreclinical TestingPredispositionPropertyProtein BiosynthesisProtein Synthesis InhibitionResearch PersonnelResistanceRibosomal ProteinsRibosomesRouteSafetySeriesSerumSiteSpectinomycinStagingStreptococcus pneumoniaeStructureTestingWorkanalogantimicrobialantimicrobial drugbasebiodefensechemical stabilitycommercializationdesigndrug candidatedrug developmentdrug discoverydrug resistant bacteriaexperienceimprovedin vitro activityin vivoneglectnovelpathogenpre-clinicalresearch studyresistance mechanismsafety testingscaffold
项目摘要
DESCRIPTION (provided by applicant): Numerically, the most successful strategy in antibacterial drug discovery has been the synthetic modification of natural products to produce new semisynthetic antibiotics. However, this approach has only been successfully applied to a few select scaffolds. Revisiting this approach, we have focused on examining the low molecular weight antibiotic spectinomycin, which we felt had been neglected, in spite of its safe pharmacological profile. Spectinomycin is an aminocyclitol antibiotic that specifically inhibits bacterial protein synthesis by binding to 30S ribosome at a unique site that is highly conserved across bacterial pathogens. Although, spectinomycin is potent in cell free assays its clinical use it restricted to second line treatment for Neisseria gonorrhoeae infections. Previous attempts to develop spectinomycin analogs, in the 1980s, led to the discovery of trospectinomycin, which showed improved activity against different bacterial pathogens and progressed into late stage clinical trials before being withdrawn for commercial reasons, validating the potential to modify this core to obtain more potent generations of drug. In view of the recent rise in multi-drug resistant bacteria that were not present when semi-synthetic broad spectrum spectinomycin analogs were last examined, we reinvestigated the potential for developing novel spectinomycin analogs as treatments for drug resistant organisms. In recent work we have found spectinomycin core tractable for advanced synthetic modifications producing several series of analogs that maintain the excellent ribosomal affinity of spectinomycin and access a unique binding pocket at the interface of 30S ribosome Helix 34 and a loop of ribosomal protein RpsE. These compounds have an excellent safety profile and far superior chemical stability to spectinomycin. In these efforts, we have recently discovered a novel series of aryl substituted aminospectinomycins with good antibacterial activities. The most potent of our compounds in our initial set demonstrate: good broad spectrum anti-bacterial activity including activity against
NIAID priority biodefense pathogens; on target inhibition of protein synthesis; good pharmacokinetic profiles; and excellent anti-S. pneumoniae activity in vivo. We believe the aminospectinomycins represent an important rediscovery of a neglected chemotype that can be used for the treatment of drug resistant and biodefense infections. The further development of this series will be pursued in three aims to: (i) Perform further structure based design and synthesis of novel aminospectinomycins with high antibacterial potency in seven targeted subseries; (ii) Confirm the mode of action of emerging leads and study the potential for cross resistance and inactivation; (iii) Perform lead development through five stages of detailed tests that include a full antimicrobial assessment, in vitro ADME, pharmacokinetic testing, toxicologic and in vivo efficacy experiments. After each stage, the data will be used to guide the design and synthesis of future generations of compounds and to select the best compounds to move on to the next stage such that viable, well characterized drug candidates will emerge from this study suitable for preclinical development.
描述(由申请人提供):从数字上讲,抗菌药物发现中最成功的策略是对天然产物进行合成修饰,以产生新的半合成抗生素。然而,这种方法仅成功应用于少数选择的支架。重新审视这种方法,我们重点研究了低分子量抗生素大观霉素,我们认为这是被忽视的,尽管其安全的药理学特征。大观霉素是一种氨基环醇抗生素,通过在细菌病原体中高度保守的独特位点与30 S核糖体结合,特异性抑制细菌蛋白质合成。尽管大观霉素在无细胞试验中是有效的,但其临床用途仅限于淋病奈瑟菌感染的二线治疗。在20世纪80年代,开发大观霉素类似物的先前尝试导致了trosectinomycin的发现,其显示出对不同细菌病原体的改善的活性,并且在由于商业原因被撤回之前进展到后期临床试验,从而验证了修饰该核心以获得更有效的药物代的潜力。鉴于最近出现的多药耐药细菌,不存在时,半合成的广谱大观霉素类似物进行了最后一次检查,我们重新研究了开发新的大观霉素类似物作为治疗耐药生物体的潜力。在最近的工作中,我们已经发现壮观霉素核心易于进行高级合成修饰,产生几个系列的类似物,这些类似物保持壮观霉素的优异核糖体亲和力,并在30 S核糖体HPLC 34和核糖体蛋白RpsE环的界面处进入独特的结合口袋。这些化合物具有优异的安全性和远优于大观霉素的上级化学稳定性。在这些努力中,我们最近发现了一系列具有良好抗菌活性的芳基取代氨基壮观霉素。在我们的初始组中,我们的化合物中最有效的化合物证明:良好的广谱抗菌活性,包括对
NIAID优先生物防御病原体;对蛋白质合成的靶向抑制;良好的药代动力学特征;以及优异的抗S。pneumoniae体内活性。我们认为,氨基壮观霉素代表了一个重要的重新发现被忽视的化学型,可用于治疗耐药性和生物防御感染。该系列的进一步开发将追求三个目标:(i)在七个靶向亚系列中进行进一步的基于结构的设计和合成具有高抗菌效力的新型氨基壮观霉素;(ii)确认新出现的先导化合物的作用模式并研究交叉耐药性和失活的潜力;(iii)通过五个阶段的详细测试进行铅的开发,包括全面的抗菌评估,体外ADME,药代动力学测试,毒理学和体内功效实验。每个阶段结束后,数据将用于指导未来几代化合物的设计和合成,并选择最好的化合物进入下一阶段,以便从本研究中产生适合临床前开发的可行且表征良好的候选药物。
项目成果
期刊论文数量(0)
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Richard E. Lee其他文献
EVALUATION OF GLYCEROL AND DIMETHYL SULFOXIDE FOR THE CRYOPRESERVATION OF SPERMATOZOA FROM THE WOOD FROG (RANA SYLVATICA)
甘油和二甲基亚砜对林蛙 (RANA SYLVATICA) 精子冷冻保存的评价
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
J. A. Mugnano;J. P. Costanzo;Sara G. Beesley;Richard E. Lee - 通讯作者:
Richard E. Lee
Carotid blood flow and pathogenesis of cerebral ischaemia
颈动脉血流与脑缺血的发病机制
- DOI:
10.1007/978-94-011-1848-4_35 - 发表时间:
1993 - 期刊:
- 影响因子:0
- 作者:
M. Aldoori;Richard E. Lee - 通讯作者:
Richard E. Lee
The Bulbar Conjunctival Vascular Bed in Normal Pregnancy
- DOI:
10.1016/s0002-9378(16)38683-5 - 发表时间:
1953-04-01 - 期刊:
- 影响因子:
- 作者:
Robert Landesman;Gordon Douglas;Georgene Dreishpoon;Richard E. Lee - 通讯作者:
Richard E. Lee
Ultrastructural effects of lethal freezing on brain, muscle and Malpighian tubules from freeze-tolerant larvae of the gall fly, Eurosta solidaginis.
致命冷冻对耐冻胆蝇幼虫脑、肌肉和马氏小管的超微结构影响。
- DOI:
10.1016/s0022-1910(96)00073-x - 发表时间:
1997 - 期刊:
- 影响因子:2.2
- 作者:
Stephen D Collins;A. Allenspach;Richard E. Lee - 通讯作者:
Richard E. Lee
An approach to combinatorial library generation of galactofuranose mimics as potential inhibitors of mycobacterial cell wall biosynthesis: Synthesis of a peptidomimetic of uridine 5′-diphosphogalactofuranose (UDP-Galf)
呋喃半乳糖模拟物作为分枝杆菌细胞壁生物合成潜在抑制剂的组合文库生成方法:尿苷 5′-二磷酸半乳呋喃糖肽模拟物的合成 (UDP-Galf)
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Richard E. Lee;Martin D. Smith;L. Pickering;G. Fleet - 通讯作者:
G. Fleet
Richard E. Lee的其他文献
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{{ truncateString('Richard E. Lee', 18)}}的其他基金
Training in the Design and Development of Infectious Disease Therapeutics
传染病治疗药物设计和开发培训
- 批准号:
10617855 - 财政年份:2015
- 资助金额:
$ 69.2万 - 项目类别:
Training in the Design and Development of Infectious Disease Therapeutics
传染病治疗药物设计和开发培训
- 批准号:
10447715 - 财政年份:2015
- 资助金额:
$ 69.2万 - 项目类别:
Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
- 批准号:
9291410 - 财政年份:2014
- 资助金额:
$ 69.2万 - 项目类别:
Development of Aminospectinomycins for Biodefense
用于生物防御的氨基大观霉素的开发
- 批准号:
8693411 - 财政年份:2014
- 资助金额:
$ 69.2万 - 项目类别:
Development of novel proteins synthesis inhibitors for MDR tuberculosis
耐多药结核病新型蛋白质合成抑制剂的开发
- 批准号:
8305156 - 财政年份:2010
- 资助金额:
$ 69.2万 - 项目类别:
Development of novel proteins synthesis inhibitors for MDR tuberculosis
耐多药结核病新型蛋白质合成抑制剂的开发
- 批准号:
7989056 - 财政年份:2010
- 资助金额:
$ 69.2万 - 项目类别:
Development of novel proteins synthesis inhibitors for MDR tuberculosis
耐多药结核病新型蛋白质合成抑制剂的开发
- 批准号:
8495235 - 财政年份:2010
- 资助金额:
$ 69.2万 - 项目类别:
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