Supramolecular Nanofibers with Superior Bioactivity to Insulin-Like Growth Factor-I.
Shang Yuna,Zhi Dengke,Feng Guowei,Wang Zhongyan,Mao Duo,Guo Shuang,Liu Ruihua,Liu Lulu,Zhang Shuhao,Sun Shenghuan,Wang Kai,Kong Deling,Gao Jie,Yang Zhimou
Bioactive peptides derived from proteins generally need to be folded into secondary structures to activate downstream signaling pathways. However, synthetic peptides typically form random-coils, thus losing their bioactivities. Here, we show that by introducing a self-assembling peptide motif and using different preparation pathways, a peptide from insulin-like growth factor-I (IGF-1) can be folded into an α-helix and β-sheet. The β-sheet one exhibits a low dissociation constant to the IGF-1 receptor (IGF-1R, 11.5 nM), which is only about 3 times higher than that of IGF-1 (4.3 nM). However, the α-helical one and the peptide without self-assembling motif show weak affinities to IGF-1R ( K = 179.1 and 321.6 nM, respectively). At 10 nM, the β-sheet one efficiently activates the IGF-1 downstream pathway, significantly enhancing HUVEC proliferation and preventing cell apoptosis. The β-sheet peptide shows superior performance to IGF-1 in vivo, and it improves ischemic hind-limb salvage by significantly reducing muscle degradation and enhancing limb vascularization. Our study provides a useful strategy to constrain peptides into different conformations, which may lead to the development of supramolecular nanomaterials mimicking biofunctional proteins.
A novel thermogel system of self-assembling peptides manipulated by enzymatic dephosphorylation.
Shang Yuna,Wang Zhongyan,Zhang Renshu,Li Xinxin,Zhang Shuhao,Gao Jie,Li Xingyi,Yang Zhimou
Chemical communications (Cambridge, England)
Supramolecular hydrogels of self-assembling peptides and thermogels are very promising for biomedical applications. However, there were no thermogels of self-assembling peptides. In this study, we reported on a novel and versatile strategy to prepare thermogels of self-assembling peptides by enzyme-instructed peptide folding and self-assembly. We synthesized two phosphorylated peptides from insulin growth factor (IGF) and the second mitochondria-derived activator of caspases (Smac) (Nap-FFGGpYGSSSRRAPQT and NBD-GFFpYGAVPIAQK, respectively), which could be converted to possible hydrogelators by enzyme-instructed self-assembly (EISA). We found that EISA using phosphatase at 4 °C resulted in peptides with a random coil conformation, which would self-assemble into worm-like micelles or very short fibers in clear solutions. At a physiological temperature of 37 °C, the peptides would undergo fast transitions from random coil to β-sheet- or α-helix-like conformations, resulting in solution-to-gel transformations. This novel thermogel system was very useful for three-dimensional (3D) cell culture due to the biocompatibility and bioactivity of peptides. Our study provides a novel strategy to prepare a novel thermogel system for biomedical applications.
Delivery of MSCs with a Hybrid β-Sheet Peptide Hydrogel Consisting IGF-1C Domain and D-Form Peptide for Acute Kidney Injury Therapy.
Wang Hongfeng,Shang Yuna,Chen Xiaoniao,Wang Zhongyan,Zhu Dashuai,Liu Yue,Zhang Chuyue,Chen Pu,Wu Jie,Wu Lingling,Kong Deling,Yang Zhimou,Li Zongjin,Chen Xiangmei
International journal of nanomedicine
Purpose:By providing a stem cell microenvironment with particular bioactive constituents in vivo, synthetic biomaterials have been progressively successful in stem cell-based tissue regeneration by enhancing the engraftment and survival of transplanted cells. Designs with bioactive motifs to influence cell behavior and with D-form amino acids to modulate scaffold stability may be critical for the development and optimization of self-assembling biomimetic hydrogel scaffolds for stem cell therapy. Materials and Methods:In this study, we linked naphthalene (Nap) covalently to a short D-form peptide (Nap-FFG) and the C domain of insulin-like growth factor-1 (IGF-1C) as a functional hydrogel-based scaffolds, and we hypothesized that this hydrogel could enhance the therapeutic efficiency of human placenta-derived mesenchymal stem cells (hP-MSCs) in a murine acute kidney injury (AKI) model. Results:The self-assembling peptide was constrained into a classical β-sheet structure and showed hydrogel properties. Our results revealed that this hydrogel exhibited increased affinity for IGF-1 receptor. Furthermore, cotransplantation of the β-IGF-1C hydrogel and hP-MSCs contributed to endogenous regeneration post-injury and boosted angiogenesis in a murine AKI model, leading to recovery of renal function. Conclusion:This hydrogel could provide a favorable niche for hP-MSCs and thereby rescue renal function in an AKI model by promoting cell survival and angiogenesis. In conclusion, by covalently linking the desired functional groups to D-form peptides to create functional hydrogels, self-assembling β-sheet peptide hydrogels may serve as a promising platform for tissue-engineering and stem cell therapy.
Nuclear delivery of dual anticancer drug-based nanomedicine constructed by cisplatinum-induced peptide self-assembly.
Xu Tengyan,Liang Chunhui,Zheng Debin,Yan Xiaorong,Chen Yaoxia,Chen Yumiao,Li Xinxin,Shi Yang,Wang Ling,Yang Zhimou
Nuclear delivery of anticancer drugs, particularly dual complementary anticancer drugs, can significantly improve chemotherapy efficacy. However, successful examples are rare. We reported a novel dual anticancer drug-based nanomedicine with nuclear accumulation properties. The nanomedicine was formed by chelation between a drug peptide amphiphile Rh-GFFYERGD (Rh represents Rhein, 1,8-dihydroxy-3-carboxy anthraquinonea) and cisplatinum (Pt). A single molecule of the drug peptide amphiphile could chelate up to 8 equiv. of cisplatinum in the resulting nanofibers. The nanofibers with a 1 : 4 ratio of Rh-GFFYERGD to cisplatinum demonstrated remarkable cellular uptake, and more significantly, superior nuclear accumulation properties. Additionally, the nanofibers could also bind to the DNA molecule more efficiently than those formed by the drug peptide amphiphile. Thus the nanofibers exhibited excellent anticancer properties both in vitro and in vivo. We envision a significant therapeutic potential of the dual anticancer drug-based nanomedicine with cisplatinum in cancer.