Jomori Takahiro, Higa Nanami, Hokama Shogo, Tyas Trianda Ayuning, Matsuura Natsuki, Ueda Yudai, Kimura Ryo, Arizono Sei, de Voogd Nicole Joy, Hayashi Yasuhiro, Yasumoto-Hirose Mina, Tanaka Junichi, Mori-Yasumoto Kanami
Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Mar Drugs. 2024 Dec 30;23(1):16. doi: 10.3390/md23010016.
Leishmaniasis is a major public health problem, especially affecting vulnerable populations in tropical and subtropical regions. The disease is endemic in 90 countries, and with millions of people at risk, it is seen as one of the ten most neglected tropical diseases. Current treatments face challenges such as high toxicity, side effects, cost, and growing drug resistance. There is an urgent need for safer, affordable treatments, especially for cutaneous leishmaniasis (CL), the most common form. Marine invertebrates have long been resources for discovering bioactive compounds such as sesterterpenoids. Using bioassay-guided fractionations against cutaneous-type leishmaniasis promastigotes, we identified a novel furanosesterterpenoid, petrosaspongin from Okinawan marine sponges and a nudibranch, along with eight known sesterterpenoids, hippospongins and manoalides. The elucidated structure of petrosaspongin features a β-substituted furane ring, a tetronic acid, and a conjugated triene. The sesterterpenoids with a γ-butenolide group exhibited leishmanicidal activity against promastigotes, with IC values ranging from 0.69 to 53 μM. The structure-activity relationship and molecular docking simulation suggest that γ-lactone is a key functional group for leishmanicidal activity. These findings contribute to the ongoing search for more effective treatments against CL.
利什曼病是一个重大的公共卫生问题，尤其影响热带和亚热带地区的弱势群体。该疾病在90个国家呈地方性流行，数百万人面临风险，被视为十大最被忽视的热带疾病之一。目前的治疗方法面临着高毒性、副作用、成本以及耐药性不断增加等挑战。迫切需要更安全、可负担得起的治疗方法，尤其是针对最常见的皮肤利什曼病（CL）。海洋无脊椎动物长期以来一直是发现生物活性化合物（如链状四萜类化合物）的资源。通过针对皮肤型利什曼病前鞭毛体进行生物测定引导的分级分离，我们从冲绳海洋海绵和一种裸鳃亚目动物中鉴定出一种新型呋喃链状四萜类化合物——petrosaspongin，以及八种已知的链状四萜类化合物、海绵素和软海绵素。已阐明的petrosaspongin结构具有一个β-取代呋喃环、一个特窗酸和一个共轭三烯。带有γ-丁内酯基团的链状四萜类化合物对前鞭毛体表现出杀利什曼活性，IC值范围为0.69至53μM。构效关系和分子对接模拟表明，γ-内酯是杀利什曼活性的关键官能团。这些发现有助于持续寻找针对皮肤利什曼病更有效的治疗方法。
