O'Brien Emily A, Purslow Jeffrey A, Wall Brendan J, VanVeller Brett
Department of Chemistry, Iowa State University Ames IA 50011 USA
Chem Sci. 2024 Oct 23;15(45):18992-9. doi: 10.1039/d4sc06108j.
Amidines are an isostere of the amide bond and are completely unexplored in peptide secondary structure. This study marks the first investigation of the structural implications of amidines in folded helices. Amidines were found to engage in hydrogen-bonding interactions that are compatible with helical structure. The protic state of the amidine is also adaptive to local interactions, able to form stronger hydrogen bonds with proton donors or form the first example of a salt bridge along the peptide backbone to stabilize the C-terminus of the helical fold. The rationalization of this behavior was aided by our discovery that the basicity of amidines within peptide backbones can be significantly lower than previously assumed for small molecules. These findings compel investigation of amidines in peptide-drug design.
脒是酰胺键的电子等排体，在肽二级结构方面完全未被探索。本研究首次调查了脒在折叠螺旋中的结构影响。发现脒参与了与螺旋结构兼容的氢键相互作用。脒的质子状态也适应局部相互作用，能够与质子供体形成更强的氢键，或者形成沿肽主链的盐桥的首个实例以稳定螺旋折叠的C端。我们发现肽主链内脒的碱性可能显著低于此前对小分子的假设，这有助于解释这种行为。这些发现促使人们在肽药物设计中对脒进行研究。
