Cleavage and polyadenylation specificity factor subunit 3 (CPSF3) (CPSF3)

Cleavage and polyadenylation specificity factor subunit 3 (CPSF3) is a zinc-dependent endonuclease essential for the survival of Leishmania parasites (Nare et al., 2022). It plays a critical role in the processing of precursor messenger RNA (pre-mRNA), specifically in the 3'-end cleavage and polyadenylation steps, as well as the unique trans-splicing mechanism found in kinetoplastids (Wall et al., 2018). By catalyzing the cleavage of the pre-mRNA chain, CPSF3 ensures the maturation of functional mRNA required for protein synthesis (UniProt). This enzyme has emerged as a high-priority therapeutic target for leishmaniasis, a neglected tropical disease caused by various Leishmania species (DNDi). Small molecule inhibitors, particularly benzoxaboroles like DNDI-6148 (Ganfeborole), have demonstrated potent antileishmanial activity by binding to the catalytic site of CPSF3 and blocking its endonuclease function (Swinney et al., 2021). Because the parasite's mRNA processing machinery differs significantly from that of the human host, CPSF3 offers a viable window for selective toxicity (Nature Communications, 2017).

Other names

CPSF-73CPSF73mRNA 3'-end-processing endonuclease CPSF3Leishmania CPSF3Cleavage and polyadenylation specificity factor 73 kDa subunit

Inhibition of the endonuclease activity of CPSF3, which prevents the processing of pre-mRNA into mature mRNA by blocking 3'-end cleavage and trans-splicing, thereby halting protein synthesis and leading to parasite death (Nare et al., 2022).