Unusual Tetrahydropyridoindole-Containing Tetrapeptides with Human Nicotinic Acetylcholine Receptors Targeting Activity Discovered from Antarctica-Derived Psychrophilic Pseudogymnoascus sp. HDN17-933

• Published in: Marine Drugs
• Main Authors: 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
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI AG 2022
• Subjects: psychrophilic fungus; tetrapeptides; tetrahydropyridoindoles unit; solid-phase synthesis; nicotinic acetylcholine receptors; molecular docking; Biology (General); QH301-705.5; Antarc*; Antarctica
• Online Access: https://doi.org/10.3390/md20100593; https://doaj.org/article/9af18c381f454058a2d69941dfca8c85

Chemical investigation of the psychrophilic fungus Pseudogymnoascus sp. HDN17-933 derived from Antarctica led to the discovery of six new tetrapeptides psegymamides A–F ( 1 – 6 ), whose planar structures were elucidated by extensive NMR and MS spectrometric analyses. Structurally, psegymamides D–F ( 4 – 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’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–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 α 4 β 2 was explained by molecular docking studies.