Khatri Bhavesh, Nuthakki Venkateswara Rao, Chatterjee Jayanta
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Methods Mol Biol. 2019;2001:17-40. doi: 10.1007/978-1-4939-9504-2_2.
Macrocyclic peptides are a unique class of molecules that display a relatively constrained peptidic backbone as compared to their linear counterparts leading to the defined 3-D orientation of the constituent amino acids (pharmacophore). Although they are attractive candidates for lead discovery owing to the unique conformational features, their peptidic backbone is susceptible to proteolytic cleavage in various biological fluids that compromise their efficacy. In this chapter we review the various classical and contemporary chemical and biological approaches that have been utilized to combat the metabolic instability of macrocyclic peptides. We note that any chemical modification that helps in providing either local or global conformational rigidity to these macrocyclic peptides aids in improving their metabolic stability typically by slowing the cleavage kinetics by the proteases.
大环肽是一类独特的分子，与线性肽相比，其肽主链相对受限，导致组成氨基酸（药效基团）具有明确的三维取向。尽管由于其独特的构象特征，它们是药物先导物发现的有吸引力的候选物，但其肽主链在各种生物流体中易受蛋白水解切割的影响，从而损害其功效。在本章中，我们综述了用于对抗大环肽代谢不稳定性的各种经典和现代化学及生物学方法。我们注意到，任何有助于为这些大环肽提供局部或整体构象刚性的化学修饰，通常通过减缓蛋白酶的切割动力学，有助于提高其代谢稳定性。
