Targeting viral envelopes with antiviral peptides and peptoids and degraders, and surface proteins with small molecules

使用抗病毒肽、类肽和降解剂以及小分子表面蛋白靶向病毒包膜

• 批准号: 10514271
• 负责人: Nam-Joon Cho
• 金额: $ 290.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514271
• 关键词: 2019-nCoV; Advanced Development; Affect; Amino Acid Substitution; Amino Acids; Antiviral Agents; COVID-19; COVID-19 pandemic; Caliber; Cell membrane; Chikungunya virus; Collaborations; Cryoelectron Microscopy; Cytolysis; Data; Dengue Virus; Development; Disease Outbreaks; Dose; Drug Kinetics; Half-Life; In Vitro; Infection; Inhalation; Intravenous; Japanese encephalitis virus; Lead; Length; Lipids; Mammalian Cell; Maximum Tolerated Dose; Membrane; Membrane Lipids; Membrane Proteins; Mission; Mus; N-substituted Glycines; Outpatients; Peptides; Peptoids; Polyethylene Glycols; Polymers; Property; RNA Viruses; Rattus; Research Personnel; Resistance; Resolution; Testing; Therapeutic; Toxic effect; Translations; Treatment Efficacy; Viral; Viremia; Virion; Virus; Work; Yellow fever virus; ZIKV infection; Zika Virus; anti-viral efficacy; biophysical properties; combat; density; experimental study; image reconstruction; in vivo; mouse model; novel; pandemic disease; resistant strain; small molecule; structural biology; subcutaneous; synergism; unnatural amino acids; virus envelope

ABSTRACT. Our overall objective is to develop a new class of direct acting-antivirals (DAAs) that can specifically target viral envelopes but not host cell membranes using our novel amphipathic, α-helical (AH) Lipid Envelope Antiviral Disruption (LEAD) peptides and peptoids (sequence-specific N-substituted glycine oligomers). Therapeutics that can specifically target enveloped viruses have the potential to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a wide variety of RNA viruses of pandemic potential. One promising target is the lipid membrane coating that surrounds enveloped viruses, as membrane disruption can abrogate viral infectivity. This team’s investigators have developed a new class of AH peptides, and another new type of self-assembling amphipathic peptoids, that selectively form pores in high-curvature membranes such as membrane-enveloped virus particles (<160 nm diameter) but do not form pores in low-curvature membranes such as those of mammalian cells. Once a critical density of pores forms in the viral membrane, pore-induced membrane lysis occurs, leading to loss of viral infectivity. We have also showed that incorporating D-amino acids (instead of natural L-amino acids) into LEAD peptides can enhance their in vivo stability. Excitingly, our preliminary data to date showed that one LEAD peptide (AH-D) has potent antiviral activity against a wide range of enveloped viruses including Zika virus (ZIKV), Dengue virus (DENV), Chikungunya virus (CHIKV), Yellow Fever virus (YFV), Japanese encephalitis virus (JEV), and SARS-CoV-2 without cellular toxicity in vitro. Even more excitingly, when administered in vivo, AH-D peptide can protect mice against lethal ZIKV infections as well as block DENV viremia. We have also recently developed novel antiviral peptoids that can similarly target viral envelopes selectively, with potent anti-SARS-CoV-2 activity. Finally, subcutaneous administration of a LEAD peptide had reasonably comparable exposure but with a longer half-life than when administered intravenously. We now seek to advance the development of a promising lead molecule by: 1) further characterizing the biophysical properties of LEAD peptides and peptoids responsible for their antiviral activity against enveloped viruses; 2) optimizing in vivo pharmacokinetics (PK) of LEAD peptides and peptoids for subcutaneous and inhalation delivery (by collaborating with Project 2) suitable for outpatient administration; 3) evaluating antiviral efficacy of the optimized LEAD peptides and peptoids in mouse models of DENV, ZIKV, and SARS-CoV-2; and 4) nominating a top-performing LEAD peptide/peptoid for IND-enabling studies by collaborating with Project 6 on mechanisms of potential resistance to our top performing molecules, conducting synergy studies with other available DAAs including ones developed in SyneRx, and beginning initial assessments of in vitro ADME and in vivo non-GLP rat toxicity. Successful completion of our aims will yield an exciting novel class of DAAs that can specifically target viral envelopes for use alone, or in combination with other DAAs, to combat SARS-CoV-2 and other infections caused by membrane-enveloped viruses with pandemic potential.

抽象的。我们的总体目标是开发新的直接表演抗毒药（DAA），可以具体 使用我们的新型两亲性α-螺旋（AH）脂质包络 抗病毒破坏（铅）宠物和胡椒（序列特异性N-取代的甘氨酸低聚物）。 可以专门靶向包膜病毒的治疗剂有可能抵消严重急性 呼吸综合征冠状病毒2（SARS-COV-2）和多种大流行潜力的RNA病毒。 一个承诺的目标是膜膜涂层，即膜破坏，周围环境包裹病毒 可以消除病毒感染。该团队的调查人员开发了新的AH肽，另一个 新型的自组装两亲性肽，在高曲率膜上有选择地形成毛孔 作为膜开发的病毒颗粒（直径<160 nm），但在低曲率膜上不形成毛孔 例如哺乳动物细胞的细胞。一旦在病毒膜中形成孔的临界密度，孔就会诱导 膜裂解发生，导致病毒感染的丧失。我们还表明，掺入D-氨基酸 （而不是天然的L-氨基酸）进入铅肽可以增强其体内稳定性。令人兴奋的是，我们的 迄今为止的初步数据表明，一个铅肽（AH-D）具有潜在的抗病毒活性。 包括寨卡病毒（ZIKV），登革热病毒（DENV），Chikungunya病毒（Chikv），黄色的包裹病毒 发烧病毒（YFV），日本脑炎病毒（JEV）和SARS-COV-2没有细胞毒性。甚至 更令人兴奋的是，当在体内给药时，AH-D Peel也可以保护小鼠免受致命的ZIKV感染。 作为块DENV病毒血症。我们最近还开发了新型的抗病毒肽，可以类似地靶向病毒 具有选择性的包络，具有潜在的抗SARS-COV-2活性。最后，皮下给药 肽具有相当可比的暴露，但半衰期比静脉内给药时更长。 现在，我们寻求通过以下方式推进有希望的铅分子的发展 铅宠物和胡椒的生物物理特性负责其抗病毒活性针对包裹 病毒； 2）优化皮下肽和肽的体内药代动力学（PK） 吸入交付（通过与项目2合作）适合门诊管理； 3）评估抗病毒 优化的铅宠物和胡椒素在DENV，ZIKV和SARS-COV-2的小鼠模型中的功效；和 4）通过与项目6合作提名表现最佳的铅辣椒/肽用于辅助研究 关于对我们最高表现分子的潜在抗性的机制，与其他 可用的DAA包括在Synerx中开发的DAA，并开始对体外ADME和IN的初步评估 体内非GLP大鼠毒性。成功完成我们的目标将产生令人兴奋的新颖的DAA类，可以 特别针对单独使用的病毒信封，或与其他DAA结合使用，以对抗SARS-COV-2和 其他具有大流行潜力的膜开发病毒引起的感染。