Structure-guided design, generation, and biofunction of PEGylated fibroblast growth factor 2 variants for wound healing

Sun, Jian; Wu, Jing; Jin, Hui; Ying, Te; Wu, Jin; Fan, Miaojuan; Zhou, Jianhui; Chen, Hui; Jin, Litai; Zhou, Jie

doi:10.1039/d0nr05999d

Cited by 7 publications

(6 citation statements)

References 41 publications

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“…As previously stated, FGF1 HBS expression and purification were carried out. 11 The amino acid and codon sequences of FGF1 ΔHBS and MT-FGF1 ΔHBS can be found in Table S1.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…Fibroblast growth factor 1 (FGF1) has been reported to be involved in various biological processes such as embryonic development, wound healing, neurogenesis, and angiogenesis. − Recently, FGF1 was identified as a metabolic hormone that plays a pivotal role in regulating insulin sensitivity, glycemic control, and nutrient stress. − A single peripheral injection of FGF1 can lower glucose to normal levels in hours without risk of hypoglycemia, while its chronic treatment achieves whole-body insulin sensitization . Thus, it is probable that FGF1 may be a promising therapeutic approach for the treatment of T2DM by targeting the skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

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Novel Muscle-Homing Peptide FGF1 Conjugate Based on AlphaFold for Type 2 Diabetes Mellitus

Zhou

Chen

et al. 2023

ACS Appl. Mater. Interfaces

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Drugs for metabolic diseases usually require systemic administration and act on multiple tissues, which may produce some unpredictable side effects. There have been many successful studies on targeted drugs, especially antitumor drugs. However, there is still little research on metabolic disease drugs targeting specific tissues. Fibroblast growth factor 1 (FGF1) is a potential therapy for type 2 diabetes (T2D) without the risk of hypoglycemia. However, the major impediment to the clinical application of FGF1 is its mitogenic potential. We previously engineered an FGF1 variant (named FGF1ΔHBS) to tune down its mitogenic activity via reducing the heparin-binding ability. However, other notable side effects still remained, including severe appetite inhibition, pathogenic loss of body weight, and increase in fatality rate. In this study, we used AlphaFold2 and PyMOL visualization tools to construct a novel FGF1ΔHBS conjugate fused with skeletal muscle-targeted (MT) peptide through a flexible peptide linker termed MT-FGF1ΔHBS. We found that MT-FGF1ΔHBS specifically homed to skeletal muscle tissue after systemic administration and induced a potent glucose-lowering effect in T2D mice without hypoglycemia. Mechanistically, MT-FGF1ΔHBS elicits the glucose-lowering effect via AMPK activation to promote the GLUT4 expression and translocation in skeletal muscle cells. Notably, compared with native FGF1ΔHBS, MT-FGF1ΔHBS had minimal effects on food intake and body weight and did not induce any hyperplasia in major tissues of both T2D and normal mice, indicating that this muscle-homing protein may be a promising candidate for T2D treatment. Our targeted peptide strategy based on computer-aided structure prediction in this study could be effectively applied for delivering agents to functional tissues to treat metabolic or other diseases, offering enhanced efficacy and reducing systemic off-target side effects.

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“…As previously stated, FGF1 HBS expression and purification were carried out. 11 The amino acid and codon sequences of FGF1 ΔHBS and MT-FGF1 ΔHBS can be found in Table S1.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Muscle-Homing Peptide FGF1 Conjugate Based on AlphaFold for Type 2 Diabetes Mellitus

Zhou

Chen

et al. 2023

ACS Appl. Mater. Interfaces

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“…BALB/c mice were first anesthetized by intraperitoneal injection of 1% sodium pentobarbital (0.005 mL g −1 ), their back hair was shaved, and the skin was disinfected with ethanol. Then, a 160 °C preheating rod was applied to the back of each mouse for 10 s, and two burns with a diameter of 5 mm were caused [ 7 ]. All mice were housed individually to prevent additional effects on the wound area.…”

Section: Methodsmentioning

confidence: 99%

“…Similar physical features are present in all types of burns, such as wound exudates and necrotizing debris on the surface. Burns involving epidermal and dermal injuries can be clinically classified as superficial second-degree burns, deep second-degree burns, and third-degree burns [ 7 , 8 ]. Medications can only improve the healing process of first-degree burns; second- and third-degree burns require immediate hospitalization [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Poloxam Thermosensitive Hydrogels Loaded with hFGF2-Linked Camelina Lipid Droplets Accelerate Skin Regeneration in Deep Second-Degree Burns

Zhang

He²,

Zhang³

et al. 2022

IJMS

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Burn injuries are difficult to manage due to the defect of large skin tissues, leading to major disability or even death. Human fibroblast growth factor 2 (hFGF2) is known to promote burn wound healing. However, direct administration of hFGF2 to the wound area would affect the bioactivity. To provide a supportive environment for hFGF2 and control its release in a steady fashion, in this research, we developed novel thermosensitive poloxam hydrogels delivered with hFGF2-linked Camelina lipid droplets (CLD-hFGF2 hydrogels). Cryopreserved scanning electron microscopy (SEM) results indicated that the incorporation of CLD-hFGF2 does not significantly affect the inner structure of hydrogels. The rheological properties showed that CLD-hFGF2 hydrogels gelated in response to temperature, thus optimizing the delivery method. In vitro, CLD-hFGF2 could be released from hydrogels for 3 days after drug delivery (the release rate was 72%), and the release solution could still promote the proliferation and migration of NIH3T3 cells. In vivo, compared with hydrogels alone or with direct CLD-hFGF2 administration, CLD-hFGF2 hydrogels had the most obvious effect on deep second-degree burn wound healing. This work indicates that CLD-hFGF2 hydrogels have potential application value in burn wound healing.

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“…Hence, more studies regarding the safety, sustained delivery, and mechanism of protein-based therapy to treat PAD are needed. Moreover, computational design to optimize the structure of the protein and increase their stability, such as conducted by Sun et al in preclinical study using modified FGF2 for wound healing 163 , also could help to solve the problem of the protein-based therapeutic angiogenesis.…”

Section: Trends In Therapeutic Angiogenesis For Padmentioning

confidence: 99%

Therapeutic angiogenesis-based strategy for peripheral artery disease

Han¹,

Luo²,

Marcelina³

et al. 2022

Theranostics

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Peripheral artery disease (PAD) poses a great challenge to society, with a growing prevalence in the upcoming years. Patients in the severe stages of PAD are prone to amputation and death, leading to poor quality of life and a great socioeconomic burden. Furthermore, PAD is one of the major complications of diabetic patients, who have higher risk to develop critical limb ischemia, the most severe manifestation of PAD, and thus have a poor prognosis. Hence, there is an urgent need to develop an effective therapeutic strategy to treat this disease. Therapeutic angiogenesis has raised concerns for more than two decades as a potential strategy for treating PAD, especially in patients without option for surgery-based therapies. Since the discovery of gene-based therapy for therapeutic angiogenesis, several approaches have been developed, including cell-, protein-, and small molecule drug-based therapeutic strategies, some of which have progressed into the clinical trial phase. Despite its promising potential, efforts are still needed to improve the efficacy of this strategy, reduce its cost, and promote its worldwide application. In this review, we highlight the current progress of therapeutic angiogenesis and the issues that need to be overcome prior to its clinical application.

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Structure-guided design, generation, and biofunction of PEGylated fibroblast growth factor 2 variants for wound healing

Abstract: Fibroblast growth factor 2 (FGF2) plays an important role in multiple physiological functions such as tissue repair. However, FGF2 has a short half-life in vivo due to protease degradation, thus...

Cited by 7 publications

References 41 publications

Novel Muscle-Homing Peptide FGF1 Conjugate Based on AlphaFold for Type 2 Diabetes Mellitus

Novel Muscle-Homing Peptide FGF1 Conjugate Based on AlphaFold for Type 2 Diabetes Mellitus

Poloxam Thermosensitive Hydrogels Loaded with hFGF2-Linked Camelina Lipid Droplets Accelerate Skin Regeneration in Deep Second-Degree Burns

Therapeutic angiogenesis-based strategy for peripheral artery disease

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