Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的发育异常
基本信息
- 批准号:10390563
- 负责人:
- 金额:$ 29.85万
- 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:2022-07-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntiviral AgentsAnusApoptosisApplications GrantsAttentionBindingBiochemicalBiologicalBiological AssayCellsCervicalCervix UteriCessation of lifeClinicalCollectionComplexCoupledCreamCrystallizationCysteineDataDrug KineticsDrug TargetingDysplasiaEpithelialEvaluationFormulationGelGenitalGenitaliaGenotypeGoalsGuidelinesHIVHumanHuman Papilloma Virus VaccineHuman PapillomavirusHuman papilloma virus infectionHuman papillomavirus 16In VitroInfectionInfectious Skin DiseasesInflammatory ResponseInvestigationLeadLesionLiver MicrosomesLotionMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of cervix uteriMeasuresMediatingMedicalMolecular WeightMorbidity - disease rateMucous MembraneMusNeoplastic Cell TransformationOintmentsOperative Surgical ProceduresPainPharmaceutical PreparationsPharmacotherapyPhasePopulationPositioning AttributeProceduresProcessPropertyProteinsSafetySeriesSkinSmall Business Innovation Research GrantSmall Molecule Chemical LibrarySolubilitySpecific qualifier valueTP53 geneTestingTherapeuticTopical agentTopical applicationToxic effectToxicologyTumor Suppressor ProteinsUBE3A geneUbiquitinationVaginaViral GenomeVirusVirus DiseasesVulvaWait TimeWomanWorkX-Ray Crystallographyadductbasecancer invasivenesscellular targetingcovalent bonddesigndrug developmentexperimental studyhigh riskin silicoin vivoinhibitorintraepithelialmenmetabolic abnormality assessmentmodel designmodel developmentmulticatalytic endopeptidase complexnovelpharmacokinetic modelphase 1 studypremalignantpreventprophylacticprotein protein interactionprototypescreeningsmall moleculesmall molecule librariesstandard of caresuccesssystemic toxicityubiquitin ligase
项目摘要
Human papillomaviruses (HPV) cause exceedingly common infections of cutaneous and
mucosal epithelia. Infection with specific “high risk” HPV genotypes can progress to pre-
malignant lesions called dysplasias, which over a period of years, can eventuate in invasive and
metastatic epithelial malignancies. Our therapeutic goal is to treat early stage infections of the
cervix, genitalia, and anus that afflict millions of women and men before these progress to invasive
cancers.
Kovina Therapeutics strategy is to eliminate HPV infection by selectively targeting the E6
protein and preventing interactions with its cellular binding partners. E6 is necessary for viral
genome replication and maintenance and is always expressed in HPV-associated dysplasia and
malignancies. We performed in silico screening of chemical libraries for small molecules that
would resemble the interface of E6 with several of its cellular partners. Our assays focused on the
protein-protein interaction of E6 with the ubiquitin ligase E6AP, which mediates ubiquitination and
proteasome mediated destruction of the tumor suppressor protein p53. Using this model, we
designed and synthesized compounds that 1) bind to HPV-16 E6 and 2) are armed with a ‘warhead’
to make a covalent bond with a specific cysteine in HPV-16 E6 binding pocket for E6AP. The
approach to identify molecules equipped with reactive warheads that mediate covalent and
irreversible binding to cysteine is exemplified in several new clinically available drugs that target
proteins previously considered undruggable. We discovered several compounds covalently bound
to E6 via this cysteine residue, block E6 interaction with E6AP, restore P53 function, and induce
death of HPV-16 expressing cells. Multiple biochemical analyses including X-ray crystallography
prove these inhibitors occupy the targeted E6 pocket and form a single adduct with this cysteine.
Iterative optimization guided by the co-crystal data enabled design and synthesis of >80 novel
compounds and has resulted chemotypes with increased activity. This one-year Phase I SBIR
proposal plans to screen our existing E6 inhibitor collection to determine their biological activities
in cell-based assays and pharmacokinetic properties that would meet FDA guidelines for a topical
agent. We will initiate drug development studies including formulation for topical application and
early stage pharmacokinetic and toxicology characterization. The success of Phase I study will
validate this antiviral strategy and position us to proceed to apply for a Phase II SBIR to perform
IND-enabling studies.
人乳头瘤病毒(HPV)引起非常常见的皮肤和组织感染,
粘膜上皮感染特定的“高危”HPV基因型可进展至
称为发育不良的恶性病变,经过数年的时间,可能最终导致侵袭性和
转移性上皮恶性肿瘤。我们的治疗目标是治疗早期感染,
子宫颈,生殖器和肛门,折磨数百万妇女和男子之前,这些进展到侵入性
癌的
Kovenant Therapeutics的策略是通过选择性靶向E6来消除HPV感染。
蛋白质,并阻止其与细胞结合伴侣的相互作用。E6是病毒所必需的
基因组复制和维持,并且总是在HPV相关的发育不良中表达,
恶性肿瘤。我们对化学文库进行了计算机筛选,寻找小分子,
类似于E6与其几个细胞伙伴的界面。我们的分析集中在
E6与泛素连接酶E6 AP的蛋白质-蛋白质相互作用,E6 AP介导泛素化,
蛋白酶体介导的肿瘤抑制蛋白p53的破坏。利用这个模型,我们
设计和合成的化合物,1)与HPV-16 E6结合,2)装备有“弹头”,
与HPV-16 E6结合口袋中的特异性半胱氨酸形成共价键,用于E6 AP。的
一种鉴定配备有反应弹头的分子的方法,
与半胱氨酸的不可逆结合在几种新的临床上可获得的药物中得到了例证,
以前被认为是不可用的蛋白质。我们发现了几种化合物
通过该半胱氨酸残基与E6结合,阻断E6与E6 AP的相互作用,恢复P53功能,并诱导
HPV-16表达细胞死亡。多种生化分析,包括X射线晶体学
证明这些抑制剂占据靶向E6口袋并与该半胱氨酸形成单一加合物。
由共晶数据引导的迭代优化使得能够设计和合成>80个新颖的
化合物,并产生具有增加的活性的化学型。为期一年的第一阶段SBIR
一项提案计划筛选我们现有的E6抑制剂收集,以确定其生物活性
在基于细胞的测定和药代动力学特性中,
剂我们会展开药物开发研究,包括局部应用的配方,
早期药代动力学和毒理学表征。I期研究的成功将
验证这种抗病毒策略,并使我们能够继续申请第二阶段SBIR,
国家研究开发扶持性研究。
项目成果
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{{ truncateString('ELLIOT J. ANDROPHY', 18)}}的其他基金
Small Molecule E6 Inhibitors to Treat Oropharyngeal Cancers Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的口咽癌
- 批准号:
10484043 - 财政年份:2022
- 资助金额:
$ 29.85万 - 项目类别:
Development of a mouse model to test HPV Antiviral compounds
开发小鼠模型来测试 HPV 抗病毒化合物
- 批准号:
10582890 - 财政年份:2022
- 资助金额:
$ 29.85万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10220227 - 财政年份:2021
- 资助金额:
$ 29.85万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10397131 - 财政年份:2021
- 资助金额:
$ 29.85万 - 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
- 批准号:
10610388 - 财政年份:2021
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Optimization of a novel series of thiazolopyridines for the treatment of SMA
用于治疗 SMA 的新型噻唑并吡啶系列的优化
- 批准号:
8892548 - 财政年份:2015
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Toward drug treatment of spinal muscular atrophy: Mechanism of action
脊髓性肌萎缩症的药物治疗:作用机制
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8823350 - 财政年份:2014
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$ 29.85万 - 项目类别:
The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
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8866202 - 财政年份:2013
- 资助金额:
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The Indiana Cutaneous Biological Research Training Program
印第安纳州皮肤生物学研究培训计划
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8827676 - 财政年份:2013
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The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
- 批准号:
10612848 - 财政年份:2013
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$ 29.85万 - 项目类别:
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