Development of a Peptide-Based Nano-Sized Cathepsin B Inhibitor for Anticancer Therapy

Abstract

Numerous cathepsin B inhibitors have been developed and are under investigation as potential cancer treatments. They have been evaluated for their ability to inhibit cathepsin B activity and reduce tumor growth. However, they have shown critical limitations, including low anticancer efficacy and high toxicity, due to their low selectivity and delivery problems. In this study, we developed a novel peptide and drug conjugate (PDC)-based cathepsin B inhibitor using cathepsin-B-specific peptide (RR) and bile acid (BA). Interestingly, this RR and BA conjugate (RR–BA) was able to self-assemble in an aqueous solution, and as a result, it formed stable nanoparticles. The nano-sized RR–BA conjugate showed significant cathepsin B inhibitory effects and anticancer effects against mouse colorectal cancer (CT26) cells. Its therapeutic effect and low toxicity were also confirmed in CT26 tumor-bearing mice after intravenous injection. Therefore, based on these results, the RR–BA conjugate could be developed as an effective anticancer drug candidate for inhibiting cathepsin B in anticancer therapy.

Role of Cathepsin B Expression in Oral Squamous Cell Carcinoma: A Comprehensive Review

“…Development of cathepsin B inhibitors: The development of cathepsin B inhibitors is an active area of research due to their potential as a therapeutic target for cancer and other diseases. Several studies have reported the development of small-molecule inhibitors of cathepsin B, including CA074, E6446, and CA045 [ 42 ]. However, none of these inhibitors have shown strong enough anticancer effects to be clinically available, and there are currently no FDA-approved cathepsin B inhibitors for cancer treatment [ 42 ].…”

“…Several studies have reported the development of small-molecule inhibitors of cathepsin B, including CA074, E6446, and CA045 [ 42 ]. However, none of these inhibitors have shown strong enough anticancer effects to be clinically available, and there are currently no FDA-approved cathepsin B inhibitors for cancer treatment [ 42 ]. Developing potent and selective low-molecular cathepsin B inhibitors relies on the detailed expertise of preferred amino acid and inhibitor residues [ 43 ].…”

“…Another study published in 2016 found that limiting the inhibitor effect to the extracellular space or preventing lysosomal exocytosis may be a better cathepsin B targeting strategy [ 41 ]. In addition, a recent study published in 2023 developed a peptide-based nano-sized cathepsin B inhibitor with a remarkable therapeutic potential and low toxicity [ 42 ]. These findings suggest that the development of cathepsin B inhibitors is a promising area of research for treating cancer and other diseases.…”

“…Several studies have reported the development of small-molecule inhibitors of cathepsin B, including CA074, E6446, and CA045 [42]. However, none of these inhibitors have shown strong enough anticancer effects to be clinically available, and there are currently no FDA-approved cathepsin B inhibitors for cancer treatment [42].…”

Smart Delivery Systems Responsive to Cathepsin B Activity for Cancer Treatment

“…Currently, CtsB is the subject of numerous studies aimed at developing inhibitors to mitigate its activity in various conditions. The efficacy of CtsB inhibition has been tested in ameliorating a spinal cord injury by inhibiting macrophage ferroptosis [15] and treating cancer through the development of small molecules, such as the Nostoc-species-derived oxadiazine Nocuolin A [16], or biologics based on peptides [17,18]. The critical roles and regulatory pathways mediated by CtsB in various forms of regulated cell death, including pyroptosis, ferroptosis, necroptosis and apoptosis [19], make this enzyme highly attractive for developing new strategies based on inhibitory approaches.…”