Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity.

Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can function in a coordinated manner to regulate diverse biological processes including insulin and leptin signaling, T-cell activation, and tumor antigen presentation, which makes them potential targets for several therapeutic applications. We have previously demonstrated that the lipidated BimBH3 peptide analogues were a new class of promising PTP1B inhibitors with once-weekly antidiabetic potency. Herein, we chemically synthesized two series of BimBH3 analogues via site-specific modification and studied their structure-activity relationship. The screened analogues S2, S6, A2-14, A2-17, A2-20, and A2-21 exhibited an improved PTP1B/TC-PTP dual inhibitory activity and achieved good stability in the plasma of mice and dogs, which indicated long-acting potential. In mouse models of type 2 diabetes mellitus (T2DM), the selected analogues S6, S7, A2-20, and A2-21 with an excellent target activity and plasma stability generated once-weekly therapeutic potency for T2DM at lower dosage (0.5 µmol/kg). In addition, evidence was provided to confirm the cell permeability and targeted enrichment of the BimBH3 analogues. In summary, we report here that site-specific modification and long fatty acid conjugation afforded cell-permeable peptidomimetic analogues of BimBH3 with enhanced stability, in vivo activity, and long-acting pharmacokinetic profile. Our findings could guide the further optimization of BimBH3 analogues and provide a proof-of-concept for PTP1B/TC-PTP targeting as a new therapeutic approach for T2DM, which may facilitate the discovery and development of alternative once-weekly anti-T2DM drug candidates.

Polyvinylpyrrolidone-Polydatin nanoparticles protect against oxaliplatin induced intestinal toxicity in vitro and in vivo.

Oxaliplatin (OXL) is a first-line drug for the treatment of colon cancer, with excellent efficacy. Intestinal toxicity is a common side effect of OXL, with unclear pathogenesis and a lack of effective treatment strategies. Polydatin (PD) has anti-inflammatory and antioxidant activities and is a potential drug for treating intestinal diseases, but its poor water solubility limits its application. In this study, polyvinylpyrrolidone (PVP) was used as a carrier to prepare nanoparticles loaded with PD (PVP-PD), with a particle size of 92.42 nm and exhibiting sustained release properties. In vitro results showed that PVP-PD protected NCM460 cells from OXL induced injury, mitochondrial membrane potential (MMP) disruption, and accumulation of reactive oxygen species (ROS). The in vivo results demonstrated the protective effect of PVP-PD on intestinal toxicity induced by OXL, such as alleviating weight loss and colon length reduction induced by OXL. Both in vivo and in vitro mechanisms indicated that OXL induced DNA damage and activated the cGAS-STING pathway, further inducing the expression of inflammatory factors such as IL-1ß and TNF-α. PVP-PD alleviated the aforementioned changes induced by OXL by inhibiting the DNA damage-cGAS-STING pathway. In summary, our study demonstrated that the DNA damage-cGAS-STING pathway was involved in OXL induced intestinal toxicity, and PVP-PD provided a potential strategy for treating OXL induced intestinal toxicity.

Silk fibroin peptide self-assembled nanofibers delivered naringenin to alleviate cisplatin-induced acute kidney injury by inhibiting mtDNA-cGAS-STING pathway.

Silk fibroin (SF) has excellent biocompatibility and biodegradability as a biomaterial. The purity and molecular weight distribution of silk fibroin peptide (SFP) make it more suitable for medical application. In this study, SFP nanofibers (molecular weight ∼30kD) were prepared through CaCl2/H2O/C2H5OH solution decomposition and dialysis, and adsorbed naringenin (NGN) to obtain SFP/NGN NFs. In vitro results showed that SFP/NGN NFs increased the antioxidant activity of NGN and protected HK-2 cells from cisplatin-induced damage. In vivo results also showed that SFP/NGN NFs protected mice from cisplatin-induced acute kidney injury (AKI). The mechanism results showed that cisplatin induced mitochondrial damage, as well as increased mitophagy and mtDNA release, which activated the cGAS-STING pathway and induced the expression of inflammatory factors such as IL-6 and TNF-α. Interestingly, SFP/NGN NFs further activated mitophagy and inhibited mtDNA release and cGAS-STING pathway. Demonstrated that mitophagy-mtDNA-cGAS-STING signal axis was involved in the kidney protection mechanism of SFP/NGN NFs. In conclusion, our study confirmed that SFP/NGN NFs are candidates for protection of cisplatin-induced AKI, which is worthy of further study.

Baicalein-loaded silk fibroin peptide nanofibers protect against cisplatin-induced acute kidney injury: Fabrication, characterization and mechanism.

Silk fibroin (SF) is a natural polymeric biomaterial widely used in the preparation of drug delivery systems. Herein, silk fibroin peptide (SFP) was self-assembled into nanofibers, encapsulated a poorly water-soluble drug baicalein (SFP/BA NFs), and then used to protect against cisplatin-induced acute kidney injury (AKI). Specifically, the SFP/BA NFs significantly enhanced the aqueous dispersity, storage stability, and in vitro antioxidant activity of BA. SFP/BA NFs increased the drug uptake and localization to mitochondria. In vitro results demonstrated that SFP/BA NFs can relieve the cisplatin-induced HK-2 cell damage, and inhibit the cisplatin-induced accumulation of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) disruption. Mechanism studies demonstrated that SFP/BA NFs may exert nephroprotective effects by inhibiting both the cisplatin-induced DNA damage and the cGAS/STING pathway activation. In vivo results showed that cisplatin treatment resulted in decreased body weight, increased serum creatinine (SCr), and increased blood urea nitrogen (BUN) levels, while SFP/BA NFs reversed the above symptoms. Furthermore, SFP/BA NFs reversed the cisplatin-induced abnormal changes of antioxidant enzymes (e.g., SOD and GSH), and inhibited the cisplatin-induced DNA damage as well as the activation of cGAS/TING. Above all, our results revealed the potential of SFP/BA NFs to protect against cisplatin-induced AKI.