Threonine peptidases as drug targets against malaria

Abstract

While PfHslV is an attractive drug target in malaria, more investigation is required to clarify its functional role in the parasite. More efforts should also be invested in assessing the plasmodial proteasome as a drug target. The few papers investigating the effect of proteasome inhibitors on different stages of the life cycle point towards important roles not only during asexual, but also in hepatic and sexual stages, in humans and the mosquito. If this holds true, this is a key argument to further develop proteasome inhibitors for use against malaria.

Tracing an allosteric pathway regulating the activity of the HslV protease

“…Most applications have focused on I, L, and V probes and sometimes, M (22,25) and A (26) methyl groups. Although these residues remain important for much of the work described here, extending 13 CH 3 labeling to threonine is critical, because the catalytic residue in HslV is T1. Therefore, we have used the assignments of I, L, V, and M methyl groups (80 of 84 methyl groups) that were obtained in the initial phases of our work along with NOE data from 13 C-edited 3D spectra (SI Appendix, Fig.…”

“…Although these residues remain important for much of the work described here, extending 13 CH 3 labeling to threonine is critical, because the catalytic residue in HslV is T1. Therefore, we have used the assignments of I, L, V, and M methyl groups (80 of 84 methyl groups) that were obtained in the initial phases of our work along with NOE data from 13 C-edited 3D spectra (SI Appendix, Fig. S3) to obtain complete assignments for all 11 T methyl groups in highly deuterated samples of HslV prepared with 13 CH 3 label at I, L, V, M, and T sites.…”

“…Analyses involving a series of single site mutants in HslV, localized to HslU binding sites or regions undergoing significant changes on HslU binding, have identified hot spots whose perturbation leads to an allosteric pathway of propagated changes in structure and ultimately, substrate proteolysis efficiency. HslV plasticity is explored through methyl-TROSY 13 C relaxation dispersion experiments that are sensitive to millisecond timescale dynamics. The data support a dynamic coupling between residues involved in both HslU and substrate binding and residues localized to the active sites of HslV that facilitate the allostery between these distal sites.…”

“…Furthermore, HslV from the malariacausing parasite Plasmodium falciparum may be an attractive antimicrobial drug target (13), especially because the HslV protease is not present in humans. In this regard, a detailed understanding of the mechanism of substrate proteolysis and the general role of dynamics in enzyme function could be important for the design of effective pharmaceuticals.…”

Broad-Spectrum Antimalarial Activity of Peptido Sulfonyl Fluorides, a New Class of Proteasome Inhibitors

“…However, by analogy, it can be assumed that it plays important roles in regulation of cell cycle progression and probably also in other regulatory processes. Such an involvement in critical housekeeping functions would be associated with a broad spectrum of activity of proteasome inhibitors against different stages of the plasmodial life cycle (19)(20)(21).…”