Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Jordi Girona, 18-26, 08034, Barcelona, Spain.
Nuclear Magnetic Resonance Facility, IQAC-CSIC, Jordi Girona, 18-26, 08034, Barcelona, Spain.
Sci Rep. 2020 Sep 2;10(1):14430. doi: 10.1038/s41598-020-71404-0.
Based on the structure of an HIV-1 entry inhibitor peptide two stapled- and a retro-enantio peptides have been designed to provide novel prevention interventions against HIV transmission. The three peptides show greater inhibitory potencies in cellular and mucosal tissue pre-clinical models than the parent sequence and the retro-enantio shows a strengthened proteolytic stability. Since HIV-1 fusion inhibitor peptides need to be embedded in the membrane to properly interact with their viral target, the structural features were determined by NMR spectroscopy in micelles and solved by using restrained molecular dynamics calculations. Both parent and retro-enantio peptides demonstrate a topology compatible with a shared helix-turn-helix conformation and assemble similarly in the membrane maintaining the active conformation needed for its interaction with the viral target site. This study represents a straightforward approach to design new targeted peptides as HIV-1 fusion inhibitors and lead us to define a retro-enantio peptide as a good candidate for pre-exposure prophylaxis against HIV-1.
基于 HIV-1 进入抑制剂肽的结构，设计了两种订书肽和一种反向对映肽，以提供针对 HIV 传播的新型预防干预措施。这三种肽在细胞和粘膜组织的临床前模型中的抑制活性均强于亲本序列，且反向对映肽具有更强的蛋白水解稳定性。由于 HIV-1 融合抑制剂肽需要嵌入膜中才能与病毒靶标正确相互作用，因此通过 NMR 光谱在胶束中确定了结构特征，并通过使用约束分子动力学计算进行了解析。亲本肽和反向对映肽均表现出与共享的螺旋-转角-螺旋构象兼容的拓扑结构，并以相似的方式在膜中组装，保持与病毒靶位相互作用所需的活性构象。这项研究代表了一种设计新型靶向肽作为 HIV-1 融合抑制剂的直接方法，并使我们将一种反向对映肽定义为 HIV-1 暴露前预防的良好候选物。
