In silico enhancement of the stability and activity of keratinocyte growth factor

Poorebrahim, Mansour; Sadeghi, Sedigheh; Ghorbani, Raziyeh; Asghari, Matin; Abazari, Mohammad Foad; Kalhor, Hourieh; Rahimi, Hamzeh

doi:10.1016/j.jtbi.2017.01.009

Cited by 17 publications

(11 citation statements)

References 44 publications

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“…As an extracellular matrix (ECM) analogue, collagen bundles provide a natural substrate for cellular attachment and proliferation (Zhou et al, ). However, the long‐term efficacy and stability of the growth factors on collagen membranes are persistent concerns (Poorebrahim et al, ). Shen and Odedra immobilized VEGF onto a collagen scaffold using N‐(3‐dimethyla‐minopropyl)‐N′‐ethylcarbodiimide hydrochloride (EDC) chemistry, which is an easy and effective approach, and they found that the immobilized VEGF promoted the penetration and proliferation of endothelial cells into the collagen, resulting in a vascularized scaffold (Odedra, Chiu, Shoichet, & Radisic, ; Shen, Shoichet, & Radisic, ).…”

Section: Introductionmentioning

confidence: 99%

The dual delivery of KGF and bFGF by collagen membrane to promote skin wound healing

Cao

et al. 2018

J Tissue Eng Regen Med

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The major challenges associated with skin regeneration can include hindered vascularization and an insufficient degree of epithelization. In view of the complexity of these processes and the control signals on which they depend, one possible solution to these limitations could be simulating normal skin development and wound repair via the exogenous delivery of multiple cytokines. Here, we report the use of keratinocyte growth factor (KGF or FGF-7) and basic fibroblast growth factor (bFGF or FGF-2) released chemically modified collagen membranes to facilitate skin wound healing. The results from in vitro studies confirmed that this system resulted in higher cellular proliferation and faster cell migration. After transplanting the biomaterial onto an excisional wound healing model, the dual growth factor group, compared with the single growth factor groups and empty control group, showed more highly developed vascular networks and organized epidermal regeneration in the wounds. As a consequence, this experimental group showed mature epidermal coverage. Overall, this novel approach of releasing growth factors from a collagen membrane opens new avenues for fulfilling unmet clinical needs for wound care.

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Section: Introductionmentioning

confidence: 99%

The dual delivery of KGF and bFGF by collagen membrane to promote skin wound healing

Cao

et al. 2018

J Tissue Eng Regen Med

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“…Our recent work confirms the ability of HB-EGF to enhance epithelial repair in chronic tympanic membrane perforations 27 and tonsillectomy wounds 11 .HB-EGF is more stable with favorable permeability compared to other proposed growth factor treatments 31 . As above, KGF has shown efficacy as a systemic therapy for oral mucositis, but due to poor stability, a short half-life, and low permeability it is not an ideal candidate for local therapy in the oral cavity 8 .…”

Section: Discussionmentioning

confidence: 99%

“…However, its failure showed that a more convenient method of administration was needed. KGF is known to have stability problems, particularly in the harsh oral environment, where peptides are exposed to salivary enzymes, and therefore is not an ideal candidate for local administration 8 .…”

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confidence: 99%

Locally administered heparin-binding epidermal growth factor-like growth factor reduces radiation-induced oral mucositis in mice

Chen

Bekale

Khomtchouk

et al. 2020

Sci Rep

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Oral mucositis refers to lesions of the oral mucosa observed in patients with cancer being treated with radiation with or without chemotherapy, and can significantly affect quality of life. There is a large unmet medical need to prevent oral mucositis that can occur with radiation either alone or in combination with chemotherapy. We investigated the efficacy of locally administered heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent epithelial proliferation and migration stimulator of the oral mucosa as a potential therapy to prevent radiation induced oral mucositis. Using a single dose (20 Gy) of radiation to the oral cavity of female C57BL/6 J mice, we evaluated the efficacy of HB-EGF treatment (5 µl of 10 µg/ml) solution. The results show that HB-EGF delivered post radiation, significantly increased the area of epithelial thickness on the tongue (dorsal tongue (42,106 vs 53,493 µm2, p < 0.01), ventral tongue (30,793 vs 39,095 µm2, *p < 0.05)) compared to vehicle control, enhanced new epithelial cell division, and increased the quality and quantity of desmosomes in the oral mucosa measured in the tongue and buccal mucosa. This data provides the proof of concept that local administration of HB-EGF has the potential to be developed as a topical treatment to mitigate oral mucositis following radiation.

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“…According to AMYPDB APR prediction results presented in Fig. 12, the concensus APRs in rhKGF are the regions RVRR (11)(12)(13)(14), NIMEIRTVAVGIVAIK (42-57), and MFVA (109-112).…”

Section: Sequence-based Detection Of Aprs In Rhkgfmentioning

confidence: 99%

Potential aggregation hot spots in recombinant human keratinocyte growth factor; a computational study

Dastjerdeh

Shokrgozar

Rahimi

et al. 2020

Preprint

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Background: Recombinant human keratinocyte growth factor is a highly aggregation-prone therapeutic protein. The high aggregation liability of rhKGF is manifested by loss of the monomeric form of the protein and accumulation of the aggregated species even at moderate temperatures. Here, we analyzed rhKGF for its vulnerability towards aggregation by detection of aggregation-prone regions (APRs) using several sequence-based computational tools including TANGO, SolubiS, ZipperDB, AGGRESCAN, Zyggregator, Camsol, PASTA, SALSA, WALTZ, SODA, Amylpred, AMYPDB, and structure-based tools including Aggrescan3D and molecular dynamics-based spatial aggregation propensity (SAP) algorithm. Results: The sequence-based prediction of APRs in rhKGF indicated that they are mainly located at positions 10-30, 40-60, 61-66, 88-120, and 130-140 which are rich in β-branched aliphatic, hydrophobic, aromatic and Glutamine/Aspargine (Q/N) residues. Mapping on the rhKGF tertiary structure revealed that most of these residues including F16-R25, I43, E45, R47-I56, F61, Y62, N66, L88-E91, E108-F110, A112, N114, T131, and H133-T140 are surface-exposed in the natively folded protein which can promote aggregation without major unfolding event or the conformational change may occur in the oligomers composed of natively folded monomers. The other regions are buried in the native state and their contribution to non-native aggregation is mediated by a preceding unfolding event in the monomeric state of the protein. The structure-based prediction of APRs using SAP tool limited the number of identified APRs to the dynamically-exposed hydrophobic residues including V12, A50, V51, L88, I89, L90, I118, L135, and I139 mediating the native-state aggregation. Conclusion: Our analysis of APRs in rhKGF identified the regions determining the intrinsic aggregation propensity in both folded (native) and unfolded state of the protein. These regions are the candidate positions for engineering the rhKGF sequence to reduce its aggregation tendency.

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In silico enhancement of the stability and activity of keratinocyte growth factor

Cited by 17 publications

References 44 publications

The dual delivery of KGF and bFGF by collagen membrane to promote skin wound healing

The dual delivery of KGF and bFGF by collagen membrane to promote skin wound healing

Locally administered heparin-binding epidermal growth factor-like growth factor reduces radiation-induced oral mucositis in mice

Potential aggregation hot spots in recombinant human keratinocyte growth factor; a computational study

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