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

**Xuewen Hou 1, Changlong Li 1, Runfang Zhang 1, Yinping Li 1, Huadong Li 1, Yundong Zhang 1, Han-Shen Tae 2, Rilei Yu 1, Qian Che 1, Tianjiao Zhu 1, Dehai Li 1,3,4,\* and Guojian Zhang 1,3,5,\***


**Abstract:** 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.

**Keywords:** psychrophilic fungus; tetrapeptides; tetrahydropyridoindoles unit; solid-phase synthesis; nicotinic acetylcholine receptors; molecular docking
