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的直接作用抗病毒药物（DAA）， 使用我们新型两亲性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-取代甘氨酸寡聚体）。 可以特异性靶向包膜病毒的治疗剂有可能抵消严重急性 呼吸道综合征冠状病毒2（SARS-CoV-2）和各种可能大流行的RNA病毒。 一个有希望的靶点是包裹包膜病毒的脂质膜， 可以消除病毒的传染性。该团队的研究人员已经开发出一类新的AH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， 作为膜包膜病毒颗粒（直径<160 nm），但在低曲率膜中不形成孔 如哺乳动物细胞的那些。一旦在病毒膜中形成临界密度的孔， 发生膜溶解，导致病毒感染性丧失。我们还发现， （而不是天然L-氨基酸）转化为LEAD肽可以增强其体内稳定性。令人兴奋的是，我们 迄今为止的初步数据表明，一种LEAD肽（AH-D）对广泛的抗病毒活性， 有包膜病毒，包括寨卡病毒（ZIKV）、登革热病毒（DENV）、基孔肯雅病毒（CHIKV）、黄 发热病毒（YFV）、日本脑炎病毒（JEV）和SARS-CoV-2体外无细胞毒性。甚至 更令人兴奋的是，当体内施用时，AH-D肽也可以保护小鼠免受致死性ZIKV感染。 称为阻断DENV病毒血症。我们最近还开发了新的抗病毒类肽， 包膜选择性，具有有效的抗SARS-CoV-2活性。最后，皮下注射电极导线 肽具有相当的暴露量，但具有比静脉内施用时更长的半衰期。 我们现在寻求通过以下方式推进有前景的先导分子的开发：1）进一步表征 LEAD肽和类肽的生物物理性质负责其抗包膜病毒活性 病毒; 2）优化LEAD肽和类肽的体内药代动力学（PK）， 吸入给药（通过与项目2合作）适合门诊给药; 3）评价抗病毒药物 优化的LEAD肽和类肽在DENV、ZIKV和SARS-CoV-2的小鼠模型中的功效;以及 4)通过与项目6合作，为IND使能研究提名一种性能最佳的LEAD肽/拟肽 对我们的顶级分子的潜在耐药性机制进行研究，与其他 可用的DAA，包括在SyneRx中开发的DAA，并开始对体外ADME和 体内非GLP大鼠毒性。成功完成我们的目标将产生一个令人兴奋的新型DAA类， 特异性靶向病毒包膜，单独使用或与其他DAA联合使用，以对抗SARS-CoV-2， 由具有大流行潜力的膜包膜病毒引起的其他感染。