Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor
Yanyun Fu, Xiao Ding, Man Zhang, Chunlei Feng, Ziqi Yan, Rui Wang, Jianyu Xu, Xiaoxia Lin, Xiaoyu Ding, Ling Wang, Yaya Fan, Taotao Li, Yushu Yin, Liang Xing, Chenxi Xu, Shan Chen, Fadi E. Pulous, David Gennert, Frank W. Pun, Petrina Kamya, Feng Ren, Alexander Aliper, Alex Zhavoronkov
Abstract
Hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitors have been approved for treating renal anemia yet have failed clinical testing for inflammatory bowel disease because of a lack of efficacy. Here we used a multimodel multimodal generative artificial intelligence platform to design an orally gut-restricted selective PHD1 and PHD2 inhibitor that exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models. Generative artificial intelligence is used to design an effective treatment for inflammatory bowel disease in preclinical models.