Leishmania donovani proteasome subunit beta type-5 (LdPSMB5)

The Leishmania donovani proteasome subunit beta type-5 (LdPSMB5) is a key catalytic component of the 20S proteasome core, specifically providing chymotrypsin-like proteolytic activity (Khare et al., 2016, Nature). This enzyme is essential for the parasite's survival, as it regulates protein turnover, cell cycle progression, and the differentiation between life stages required for infection (Wyllie et al., 2018, Nature). The interface between the beta-4 and beta-5 subunits (β4/β5 interface) has emerged as a critical site for drug discovery because it contains a parasite-specific pocket not found in the human proteasome (Nagle et al., 2020, J. Med. Chem.). Small molecule inhibitors like LXE408 (Iclepatstat) bind at this interface, effectively blocking the proteasome's function and leading to the accumulation of toxic protein aggregates within the parasite (Brand et al., 2021, J. Med. Chem.). This selective targeting minimizes cross-reactivity with the human host proteasome, reducing the risk of side effects typically associated with proteasome inhibitors used in oncology. Consequently, this target is a primary focus for developing oral treatments for visceral leishmaniasis, a severe and often fatal form of the disease.

Other names

Ldβ5Proteasome subunit beta type-5Chymotrypsin-like subunit20S proteasome beta 5 subunitLeishmania donovani PSMB5Leishmania donovani proteasome β5 subunit at the β4/β5 interface

Selective non-competitive inhibition of the chymotrypsin-like activity of the 20S proteasome by binding to a parasite-specific pocket at the β4/β5 subunit interface (Khare et al., 2016, Nature; Nagle et al., 2020, J. Med. Chem.).