Reddy Damodara N, Singh Sukrit, Ho Chris M W, Patel Janki, Schlesinger Paul, Rodgers Stephen, Doctor Allan, Marshall Garland R
Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Eur J Med Chem. 2018 Apr 10;149:193-210. doi: 10.1016/j.ejmech.2018.02.057. Epub 2018 Feb 20.
Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)-NHCHCHOH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)-OBu channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A.
短杆菌肽A是一种由L型和D型氨基酸交替构成的外用抗生素，其特点是具有宽阔的中心孔；插入细胞膜后，它会形成破坏离子梯度的通道。我们展示了具有这种宽阔中心孔特征的螺旋拟肽，这些拟肽旨在模拟短杆菌肽A通道。拟肽是通过分子建模设计的，重点是脯氨酸类似物（特别是氮杂脯氨酸，AzPro）的杂手性二肽低聚物。在水中的分子动力学模拟证实了所设计螺旋的稳定性。合成了一个十六残基的甲酰基-（AzPro-Pro）-NHCHCHOH螺旋以及一个完整的三十二残基的Cbz-（AzPro-Pro）-OBu通道。未观察到脂质体裂解活性，这表明缺乏通道形成，可能是由于膜中不合适的氢键相互作用。与短杆菌肽A不同，这些拟肽也不会使红细胞溶血。
