| dc.description.abstract | Human diseases caused by the genus Trypanosoma, including Chagas disease and African sleeping sickness, affect millions of people and cause enormous socioeconomic burdens in impoverished areas. However, neither vaccines nor well-tolerated therapies are currently available for prevention or treatment of these neglected diseases. The trypanosomal cysteine proteases play key roles in the life cycles of the parasites, and accordingly, become promising targets of drug discovery for these diseases.
The peptidomimetic vinyl sulfone K11777 is a well characterized covalent inactivator of cruzain, the major cysteine protease of Trypanosoma cruzi. However, its irreversible mode of action may be associated with safety issues that impede its progression to clinical trials. We designed and synthesized a novel class of peptidomimetic vinyl heterocyclic inhibitors (PVHIs) which contain less electrophilic bioisosteres in place of the vinyl sulfone warheads. A number of PVHIs exerted potent, time-dependent, but reversible, inhibition of cruzain; and some of them exhibited considerable anti-trypanosomal activity not only in axenic cultures of pathogenic trypanosomes, but also in an infection model with murine cardiomyoblasts. Moreover, the concept of reversible covalent inactivation by vinyl heterocycles is herein embodied, and is potentially applicable to other enzymes containing active-site cysteines.
Cruzain is also effectively inhibited by simple peptidyl aldehydes which also raise concerns about potential toxicity and metabolic instability due to the over-reactive aldehyde group. We introduced a phenol group into the molecules that could form hemiacetal with the aldehyde group and function as a masking strategy. The hemiacetal proved to be in cyclic form until binding to cruzain which apparently promoted the ring-opening and liberated the aldehyde for reacting with the active-site cysteine. These self-masked aldehyde inhibitors (SMAIs) appeared to be potent, rapidly reversible inhibitors that also showed promising trypanocidal activity. The hemiacetal hydroxyl group of SMAIs was next derivatized to provide potential prodrugs that could be metabolized by host enzymes. Furthermore, the SMAI strategy also enlightened the design of inhibitors for SARS-CoV-2 cysteine protease, leading to a class of potent 2-pyridone-based inhibitors, of which the binding modes with the 3C-like protease were demonstrated by crystallography. | en |
