Cleavage and polyadenylation specificity factor 73 kDa subunit (CPSF3) (CPSF3)

Trypanosoma brucei Cleavage and Polyadenylation Specificity Factor 3 (CPSF3) is a zinc-dependent metallo-beta-lactamase-like endonuclease essential for the survival of the parasite (Nare et al., 2017). It plays a critical role in the processing of precursor messenger RNA (pre-mRNA), specifically in the 3'-end cleavage and polyadenylation steps (Wall et al., 2018). In kinetoplastids like T. brucei, CPSF3 is also uniquely involved in the coupled process of trans-splicing, which is vital for the maturation of nearly all protein-coding transcripts (Hendriks et al., 2003). Because of its central role in gene expression and its structural differences from the human ortholog, it has emerged as a high-priority therapeutic target (Swinney et al., 2020). Small molecule inhibitors, particularly oxaboroles like AN15368 (DNDi-6148), have demonstrated potent activity by binding to the catalytic site and blocking mRNA maturation (Zhang et al., 2017). This inhibition leads to a rapid cessation of protein synthesis and subsequent parasite death, making it a promising target for treating Human African Trypanosomiasis (DNDi, 2021). The target's specificity is enhanced by the unique trans-splicing mechanism in trypanosomes, which is absent in human hosts (Palenchar & Bellofatto, 2006). Structural studies have confirmed that these inhibitors coordinate with the catalytic zinc ions in the active site, providing a clear mechanism for drug action (Wall et al., 2018).

Other names

CPSF73Cleavage and polyadenylation specificity factor subunit 3mRNA 3'-end-processing endonuclease CPSF3Metallo-beta-lactamase domain-containing protein

Inhibition of the endonuclease activity of CPSF3, which blocks pre-mRNA processing and trans-splicing, leading to the accumulation of unprocessed transcripts and parasite death.