Development of Improved HIV-1 Capsid Inhibitors
改进的 HIV-1 衣壳抑制剂的开发
基本信息
- 批准号:10700506
- 负责人:
- 金额:$ 24.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-04 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcademiaAnti-Retroviral AgentsAntiviral AgentsBindingBiochemicalBiochemistryBiological AssayBiologyCapsidCapsid ProteinsCell Culture TechniquesCellsChemical StructureClinical TrialsComplementCoupledDataDevelopmentDoseDrug IndustryDrug TargetingDrug resistanceElectrostaticsGenerationsGoalsHIVHIV resistanceHIV-1HIV-1 drug resistanceHydrophobicityInfectionInvestigationLeadLife Cycle StagesModificationMulti-Drug ResistancePatientsPersonsPharmaceutical ChemistryPhase II/III Clinical TrialPhenotypeProcessProteinsPublishingReagentResearchResistanceResistance profileResolutionRoentgen RaysRoleScanningScienceStructureStructure-Activity RelationshipSurface Plasmon ResonanceTestingVariantViralViral PhysiologyVirusVirus ReplicationX-Ray Crystallographyanalogbasecytotoxicitydesigndrug resistant virusexperienceexperimental studyfollow-upfunctional groupgag Gene Productsimprovedinhibitormultimodalitynovelpreventrational designscreeningsmall moleculestructural biologysubcutaneousvirology
项目摘要
ABSTRACT
The HIV-1 capsid protein (CA) is an attractive target for the development of novel antiretrovirals due to its
essential and multifaceted roles in the virus biology. Lenacapavir (LEN) is a recently discovered first-in-class,
long-acting capsid-targeting inhibitor with picomolar potency against HIV-1. Phase 2/3 clinical trials have
revealed that subcutaneous administration of LEN with a six-month dosing interval enables high rates of HIV-1
suppression in heavily treatment-experienced patients infected with multi-drug resistant viral phenotypes. These
findings have highlighted LEN as a promising agent that could complement current antiretroviral compounds to
treat people living with HIV-1. However, cell culture-based viral breakthrough assays and clinical trials have
identified a number of CA substitutions that confer substantial resistance to LEN. Specifically, Q67H/N74D and
M66I substitutions emerged as major drug-resistance associated variants. Therefore, there is a need to develop
improved LEN analogs with a higher barrier to resistance. We have established synthesis of LEN in academic
setting by utilizing a modular approach of independently preparing three unique LEN subunits (A, B, and C) from
commercially available reagents. Such modular approach allows for straightforward modifications of each
subunit which can then be combined in any order to prepare LEN and its analogs. Thus, our medicinal chemistry
strategy is highly advantageous for analog development. Our complementary virology, biochemistry and
structural biology experiments have allowed us to characterize a multi-modal mechanism of action of LEN.
Furthermore, we have recently determined high-resolution X-ray crystal structures of CA hexamers containing
major drug-resistance associated Q67H/N74D and M66I changes. We propose to exploit these findings to
rationally develop improved LEN analogs with a higher barrier to resistance. In Aim 1, our efforts will focus on
modifications to LEN subunits A and C to overcome steric hindrance and electrostatic repulsions created by the
drug resistant Q67H/N74D CA variant. In aim 2, we will use our recent promising findings from MiniFrags
screening studies, which identified fragments that bind to the CA hydrophobic pocket in close vicinity to LEN.
We will synthesize new chemotypes by connecting these fragments to LEN to generate second-generation
analogs to target the major drug-resistant M66I variant. Newly synthesized compounds from both Aims 1 and 2
will be evaluated by a stepwise approach using antiviral activity, cytotoxicity, surface plasmon resonance and X-
ray crystallography to identify and characterize the lead compound(s). Taken together, the proposed research is
expected to generate novel chemotypes with improved antiviral activities against major drug resistant CA
variants that confer substantial resistance to parental LEN.
抽象的
HIV-1衣壳蛋白(CA)是由于其开发新型抗逆转录病毒的有吸引力的靶标
病毒生物学中必不可少的多方面角色。 Lenacapavir(Len)是最近发现的第一类,
具有皮摩尔效力对HIV-1的长效capsid靶向抑制剂。 2/3期临床试验具有
揭示了六个月给药间隔的皮下给药可使HIV-1的率高
受到多药耐药病毒表型感染的严重治疗经验的患者的抑制。这些
调查结果强调了Len是一种有前途的药物,可以补充电流抗逆转录病毒化合物
对待患有HIV-1的人。但是,基于细胞培养的病毒突破测定和临床试验具有
确定了许多赋予LEN耐药性的CA取代。具体来说,Q67H/N74D和
M66i取代是主要的抗药性相关变体。因此,有必要发展
改善了LEN类似物,具有更高的阻力障碍。我们已经建立了学术中Len的合成
通过利用模块化方法的设置,以独立准备三个独特的Len亚基(a,b和c)
市售试剂。这种模块化方法可以直接修改每种
然后可以按任何顺序组合来准备Len及其类似物的亚基。因此,我们的药物化学
策略对于模拟发展非常有利。我们的互补病毒学,生物化学和
结构生物学实验使我们能够表征LEN的多模式作用机理。
此外,我们最近确定了含有Ca六聚体的高分辨率X射线晶体结构
主要耐药性Q67H/N74D和M66I变化。我们建议将这些发现剥削
合理地发展了改善的LEN类似物,具有较高的阻力障碍。在AIM 1中,我们的努力将重点放在
修改LEN亚基A和C,以克服空间的障碍和静电排斥。
耐药Q67H/N74D CA变体。在AIM 2中,我们将使用Minifrags最近有前途的发现
筛选研究,发现与Len附近与Ca疏水口袋结合的片段。
我们将通过将这些片段连接到LEN来生成第二代,从而综合新的化学型
靶向主要耐药的M66I变体的类似物。来自目标1和2的新合成化合物
将通过使用抗病毒活性,细胞毒性,表面等离子体共振和X-来评估
射线晶体学以识别和表征铅化合物。综上所述,拟议的研究是
预计将产生新型的化学型,以改善对主要耐药性CA的抗病毒活性
赋予父母Len的强大抗性的变体。
项目成果
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