School of Environment and Science, Griffith University, Gold Coast, Queensland 4222, Australia.
Griffith Institute for Drug Discovery, Griffith University,Nathan, Queensland 4111, Australia.
J Nat Prod. 2023 Sep 22;86(9):2216-2227. doi: 10.1021/acs.jnatprod.3c00633. Epub 2023 Aug 23.
Six new thiazole-containing cyclic peptides, the cyclotheonellazoles D-I (-), were isolated from the Australian marine sponge sp. (2131) with their structures assigned by comprehensive 1D and 2D NMR spectroscopic and MS spectrometric analyses, Marfey's derivatization studies, and comparison with time-dependent density functional theory (TDDFT) calculated ECD data. The Type 2 azole-homologated peptides herein comprise up to five nonproteinogenic amino acids, including the protease transition state mimic α-keto-β-amino acid residue 3-amino-4-methyl-2-oxohexanoic acid (Amoha), while - also contain a terminal hydantoin residue not previously found in cyclotheonellazoles. The keramamides A () and L () were reisolated affording expanded exploration of their biological activities. The peptides were examined for protease inhibitory activities against two mammalian serine proteases (elastase and chymotrypsin) and SARS-CoV-2 3-chymotrypsin-like protease (3CL), a validated antiviral therapeutic target for COVID-19. Peptides - and keramamide A () displayed potent nanomolar inhibition of elastase (IC 16.0 to 61.8 nM), while also contained modest inhibition of chymotrypsin and SARS-CoV-2 3CL (IC 0.73 and 1.1 μM, respectively). The cyclotheonellazoles D-E (-) do not affect the viability of human breast, ovarian, and colon cancer cells (>100 μM), with the cytotoxicity previously reported for keramamide L () not replicated (inactive >20 μM).
六种新的噻唑环肽，环硫唑 D-I(-)，从澳大利亚海洋海绵中分离得到，其结构通过全面的 1D 和 2D NMR 光谱和 MS 光谱分析、Marfey 衍生化研究以及与时间相关的密度泛函理论 (TDDFT) 计算的 ECD 数据进行了确定。本文中的 2 型唑同系物肽包含多达五个非天然氨基酸，包括蛋白酶过渡态模拟物 α-酮-β-氨基酸残基 3-氨基-4-甲基-2-氧代己酸 (Amoha)，而 - 还含有一个以前在环硫唑中未发现的末端海因残基。重新分离出角质酰胺 A()和 L()，从而扩大了对其生物活性的探索。这些肽被检测对两种哺乳动物丝氨酸蛋白酶 (弹性蛋白酶和糜蛋白酶) 和 SARS-CoV-2 3-糜蛋白酶样蛋白酶 (3CL) 的蛋白酶抑制活性，3CL 是 COVID-19 的一种经过验证的抗病毒治疗靶点。肽 - 和角质酰胺 A()对弹性蛋白酶显示出很强的纳摩尔抑制作用 (IC 16.0 至 61.8 nM)，而 - 还对糜蛋白酶和 SARS-CoV-2 3CL 具有适度的抑制作用 (IC 分别为 0.73 和 1.1 μM)。环硫唑 D-E(-)不影响人乳腺癌、卵巢癌和结肠癌细胞的活力 (>100 μM)，而以前报道的角质酰胺 L()的细胞毒性没有被复制 (>20 μM 无活性)。
