在CDR中进行结构引导突变,以增强中和SARS-CoV-2纳米体的亲和力
Vishakha Singh1, Mandar Bhutkar1, Shweta Choudhary1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Uttarakhand, India.
Biochemical and biophysical research communications
|October 4, 2024
概括
这项研究设计了抗体结合区域,以增强对SARS-CoV-2的亲和力. 一种计算方法确定了突变,导致一种高效的抗体变体用于病毒中和.
科学领域:
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
- 计算生物学 计算生物学
背景情况:
- 抗体优化对于开发先进疗法至关重要.
- 针对SARS-CoV-2尖端蛋白的受体结合域 (RBD) 是抗病毒策略的关键.
研究的目的:
- 改进和设计抗体互补性确定区域 (CDRs),以提高亲和力和特异性.
- 开发一种计算管道,以加速针对SARS-CoV-2的抗体发现.
主要方法:
- 在的亲和力成熟和结构引导的CDR突变的虚拟库选.
- 蛋白质-蛋白质对接,分子动力学 (MD) 模拟和异热定位热量计 (ITC) 用于结合分析.
- 基于伪病毒的中和试验用于评估工程抗体的疗效.
主要成果:
- 选了112个单个CDR突变的虚拟库,通过对接识别了32个潜在候选者.
- 九种突变体经历了MD模拟,六种突变体通过ITC与本地纳米体相比显示了增强的结合亲和力.
- Leu106Thr突变体表现出优异的SARS-CoV-2中和,其IC50为~0.03μM,与原生纳米体的~0.77μM相比.
结论:
- 结合基于结构的设计和热力学分析的计算管道可以简化抗体的开发.
- 工程抗体显示出针对SARS-CoV-2和其他病原体的治疗干预的巨大潜力.
- 这种方法有助于快速开发针对新兴传染病的向抗体疗法.
相关概念视频
00:56Viral Structure
Viruses are extraordinarily diverse in shape and size, but they all have several structural features in common. All viruses have a core that contains a DNA- or RNA-based genome. The core is surrounded by a protective coat of proteins called the capsid. The capsid is composed of subunits called capsomeres. The capsid and genome-containing core are together known as the nucleocapsid.
02:38S-Cdk Initiates DNA Replication
The cell cycle is a series of events leading to DNA duplication followed by the division of cell content to form two daughter cells. The cell cycle progresses in four stages—the cell increases in size (gap 1 or G1-phase), duplicates its DNA (synthesis or S-phase), prepares to divide (gap 2 or G2-phase), and divides (mitosis or M-phase).
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of replication.
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of replication.
02:15M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
01:25Structure of Cadherins
The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins” is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This diversity of cadherins...
02:38S-Cdk Initiates DNA Replication
The cell cycle is a series of events leading to DNA duplication followed by the division of cell content to form two daughter cells. The cell cycle progresses in four stages—the cell increases in size (gap 1 or G1-phase), duplicates its DNA (synthesis or S-phase), prepares to divide (gap 2 or G2-phase), and divides (mitosis or M-phase).
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of replication.
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of replication.
02:15M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...