Induced Disassembly of a Virus-like Particle under Physiological Conditions for Venom Peptide Delivery,Bioconjugate Chemistry

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Induced Disassembly of a Virus-like Particle under Physiological Conditions for Venom Peptide Delivery
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-12-11 , DOI: 10.1021/acs.bioconjchem.0c00494
M Patrick Kelly _{1,

2} , Tanya Napolitano _{1,

2} , Prachi Anand ₁ , Justin S K Ho ₁ , Shakeela Jabeen _{1,

2} , Jessica Kuppan ₁ , Sujoy Manir ₁ , Mandë Holford _{1,

2,

3,

4}

Affiliation

Virus-like particles (VLPs) show considerable promise for the in vivo delivery of therapeutic compounds such as bioactive venom peptides. While loading and targeting protocols have been developed for numerous VLP prototypes, induced disassembly under physiological conditions of neutral pH, moderate temperature, and aqueous medium remain a challenge. Here, we implement and evaluate a general mechanism, based on ring-opening metathesis polymerization (ROMP), for controllable VLP disassembly. This mechanism is independent of cell-specific factors or the manipulation of environmental conditions such as pH and temperature that cannot be readily controlled in vivo. The ROMP substrate norbornene is covalently conjugated to surface-exposed lysine residues of a P22 bacteriophage-derived VLP, and ROMP is induced by treatment with the water-soluble ruthenium catalyst AquaMet. Disruption of the P22 shell and release of a GFP reporter is confirmed via native agarose electrophoresis, TEM, and dynamic light scattering (DLS) analyses. Our ROMP disassembly strategy does not depend on the particular structure or morphology of the P22 nanocontainer and is adaptable to other VLP prototypes for the potential delivery of venom peptides for pharmacological applications.

中文翻译：

在用于毒液肽递送的生理条件下诱导病毒样颗粒的分解

病毒样颗粒 (VLP)在体内递送治疗性化合物（例如生物活性毒液肽）方面显示出相当大的前景。虽然已经为许多 VLP 原型开发了加载和靶向协议，但在中性 pH、中等温度和水性介质的生理条件下诱导分解仍然是一个挑战。在这里，我们实施和评估了一种基于开环复分解聚合（ROMP）的通用机制，用于可控的 VLP 分解。这种机制独立于细胞特异性因素或无法在体内轻易控制的环境条件（如 pH 值和温度）的操纵。ROMP 底物降冰片烯与 P22 噬菌体衍生的 VLP 表面暴露的赖氨酸残基共价结合，并且通过用水溶性钌催化剂 AquaMet 处理诱导 ROMP。通过天然琼脂糖电泳、TEM 和动态光散射 (DLS) 分析证实了 P22 壳的破坏和 GFP 报告基因的释放。我们的 ROMP 分解策略不依赖于 P22 纳米容器的特定结构或形态，并且适用于其他 VLP 原型，以用于药理学应用的毒液肽的潜在递送。

更新日期：2021-01-20

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