Unusual Tetrahydropyridoindole-Containing Tetrapeptides with Human Nicotinic Acetylcholine Receptors Targeting Activity Discovered from Antarctica-Derived Psychrophilic Pseudogymnoascus sp. HDN17-933
Xuewen Hou; Changlong Li; Runfang Zhang; Yinping Li; Huadong Li; Yundong Zhang; Han-Shen Tae; Rilei Yu; Qian Che; Tianjiao Zhu; Dehai Li; Guojian Zhang
Chemical investigation of the psychrophilic fungus Pseudogymnoascus sp. HDN17-933 derived from Antarctica led to the discovery of six new tetrapeptides psegymamides A&ndash:F (1&ndash:6), whose planar structures were elucidated by extensive NMR and MS spectrometric analyses. Structurally, psegymamides D&ndash:F (4&ndash:6) possess unique backbones bearing a tetrahydropyridoindoles unit, which make them the first examples discovered in naturally occurring peptides. The absolute configurations of structures were unambiguously determined using solid-phase total synthesis assisted by Marfey&rsquo:s method, and all compounds were evaluated for their inhibition of human (h) nicotinic acetylcholine receptor subtypes. Compound 2 showed significant inhibitory activity. A preliminary structure&ndash:activity relationship investigation revealed that the tryptophan residue and the C-terminal with methoxy group were important to the inhibitory activity. Further, the high binding affinity of compound 2 to h&alpha:4&beta:2 was explained by molecular docking studies.
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