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.

摘要：我们的总体目标是开发一类新型直接作用抗病毒药物（DAA），它可以特异性地发挥作用。 使用我们的新型两亲性 α-螺旋 (AH) 脂质包膜靶向病毒包膜，而不是宿主细胞膜 抗病毒破坏 (LEAD) 肽和类肽（序列特异性 N 取代甘氨酸寡聚物）。 专门针对包膜病毒的治疗方法有可能对抗严重的急性 呼吸综合征冠状病毒 2 (SARS-CoV-2) 和多种具有大流行潜力的 RNA 病毒。 一个有希望的目标是包膜病毒周围的脂质膜涂层，因为膜破坏 该团队的研究人员开发了一种新的 AH 肽和另一种肽。 新型自组装两亲性类肽，可选择性地在高曲率膜中形成孔，例如 作为膜包膜病毒颗粒（直径<160 nm），但在低曲率膜中不形成孔 例如哺乳动物细胞中的孔洞一旦在病毒膜中形成临界密度，就会产生孔洞诱导。 发生膜裂解，导致病毒感染性丧失。我们还表明，掺入 D-氨基酸。 （而不是天然的 L-氨基酸）进入 LEAD 肽可以增强其体内稳定性。 迄今为止的初步数据表明，一种 LEAD 肽 (AH-D) 对多种病毒具有有效的抗病毒活性。 包膜病毒，包括寨卡病毒 (ZIKV)、登革热病毒 (DENV)、基孔肯雅病毒 (CHIKV)、黄病毒 发热病毒（YFV）、日本脑炎病毒（JEV）和 SARS-CoV-2 在体外无细胞毒性。 更令人兴奋的是，在体内给药时，AH-D 肽还可以保护小鼠免受致命的 ZIKV 感染 我们最近还开发了新型抗病毒肽，可以同样靶向病毒。 选择性包膜，具有有效的抗 SARS-CoV-2 活性 最后，皮下注射 LEAD。 肽的暴露量相当可比，但半衰期比静脉注射时更长。 我们现在寻求通过以下方式推进有前途的先导分子的开发：1）进一步表征 LEAD 肽和类肽的生物物理特性决定了它们对包膜病毒的抗病毒活性 2) 优化 LEAD 肽和类肽的皮下和体内药代动力学 (PK) 适合评估门诊给药的吸入给药（与项目 2 合作）；3) 抗病毒治疗； 优化的 LEAD 肽和类肽在 DENV、ZIKV 和 SARS-CoV-2 小鼠模型中的功效； 4) 通过与项目 6 合作，提名性能最佳的 LEAD 肽/类肽用于支持 IND 的研究 研究我们的顶级分子的潜在耐药机制，与其他分子进行协同研究 可用的 DAA，包括在 SyneRx 中开发的 DAA，并开始对体外 ADME 和体内的初步评估 体内非 GLP 大鼠毒性的成功实现将产生一类令人兴奋的新型 DAA。 专门针对病毒包膜，单独使用或与其他 DAA 组合使用，以对抗 SARS-CoV-2 和 由膜包膜病毒引起的具有大流行潜力的其他感染。