哈佛干细胞研究所Suneet Agarwal研究组的一项工作开发出了一种PAPD5小分子抑制剂，可用于恢复病人干细胞的端粒酶活性。该研究于2020年4月21日在线发表在《细胞—干细胞》上。

Title: Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

Author: Neha Nagpal, Jianing Wang, Jing Zeng, Emily Lo, Diane H. Moon, Kevin Luk, Roman O. Braun, Lauri M. Burroughs, Sioban B. Keel, Christopher Reilly, R. Coleman Lindsley, Scot A. Wolfe, Albert K. Tai, Patrick Cahan, Daniel E. Bauer, Yick W. Fong, Suneet Agarwal

Issue&Volume: 2020-04-21

Abstract: Genetic lesions that reduce telomerase activity inhibit stem cell replication andcause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonaryfibrosis (PF). Modalities to restore telomerase in stem cells throughout the bodyremain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstratetelomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomeraseRNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restoredtelomerase activity and telomere length in DC patient induced pluripotent stem cells.When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with arepurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3′ end maturationand telomere length. These findings pave the way for developing systemic telomeretherapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-relateddiseases.

DOI: 10.1016/j.stem.2020.03.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30138-7