Cell Penetrating Peptides as Efficient Nanocarriers for Delivery of Antifungal Compound, Natamycin for the Treatment of Fungal Keratitis

Jain, Aastha; Shah, Sushmita G; Chugh, Archana

doi:10.1007/s11095-014-1586-x

Cited by 38 publications

(19 citation statements)

References 33 publications

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“…Here, we adopted a different strategy based on the use of CPPs as delivery vehicles. Many organic molecules, such as the anticancer drug doxorubicin (74) or the antifungal drug natamycin (75), have been successfully delivered by CPPs and their therapeutic efficacy has been increased. Recently, Abushahba et al (76) used CPPs to deliver peptide nucleic acids (PNAs) targeting bacterial genes, such as RNA polymerase, to kill Listeria monocytogenes in vitro, or in cell culture and in C. elegans infection models.…”

Section: Discussionmentioning

confidence: 99%

Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

Gomarasca

Martins

Greune

et al. 2017

Antimicrob Agents Chemother

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Commonly used antimicrobials show poor cellular uptake and often have limited access to intracellular targets, resulting in low antimicrobial activity against intracellular pathogens. An efficient delivery system to transport these drugs to the intracellular site of action is needed. Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm. Here, we characterized two CPPs, ␣1H and ␣2H, derived from the Yersinia enterocolitica YopM effector protein. These CPPs, as well as Tat (trans-activator of transcription) from HIV-1, were used to deliver the antibiotic gentamicin to target intracellular bacteria. The YopM-derived CPPs penetrated different endothelial and epithelial cells to the same extent as Tat. CPPs were covalently conjugated to gentamicin, and CPP-gentamicin conjugates were used to target infected cells to kill multiple intracellular Gram-negative pathogenic bacteria, including Escherichia coli K1, Salmonella enterica serovar Typhimurium, and Shigella flexneri. Taken together, CPPs show great potential as delivery vehicles for antimicrobial agents and may contribute to the generation of new therapeutic tools to treat infectious diseases caused by intracellular pathogens.

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Section: Discussionmentioning

confidence: 99%

Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

Gomarasca

Martins

Greune

et al. 2017

Antimicrob Agents Chemother

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“…In the era of drug resistance, where pathogen membrane provides a significant barrier, intracellular delivery of antibiotics/drugs by the virtue of CPP, proved to be a vital step in combating drug resistance to some extent (Sparr et al, 2013 ). CPP based conjugates (Ganguly et al, 2008 ; Jain et al, 2015 ) and combination therapy has been explored against several resistant pathogens (Randhawa et al, 2016 ). They have been proved effective against intracellular pathogens too (Gomarasca et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Prediction of Cell-Penetrating Potential of Modified Peptides Containing Natural and Chemically Modified Residues

et al. 2018

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Designing drug delivery vehicles using cell-penetrating peptides is a hot area of research in the field of medicine. In the past, number of in silico methods have been developed for predicting cell-penetrating property of peptides containing natural residues. In this study, first time attempt has been made to predict cell-penetrating property of peptides containing natural and modified residues. The dataset used to develop prediction models, include structure and sequence of 732 chemically modified cell-penetrating peptides and an equal number of non-cell penetrating peptides. We analyzed the structure of both class of peptides and observed that positive charge groups, atoms, and residues are preferred in cell-penetrating peptides. In this study, models were developed to predict cell-penetrating peptides from its tertiary structure using a wide range of descriptors (2D, 3D descriptors, and fingerprints). Random Forest model developed by using PaDEL descriptors (combination of 2D, 3D, and fingerprints) achieved maximum accuracy of 95.10%, MCC of 0.90 and AUROC of 0.99 on the main dataset. The performance of model was also evaluated on validation/independent dataset which achieved AUROC of 0.98. In order to assist the scientific community, we have developed a web server “CellPPDMod” for predicting the cell-penetrating property of modified peptides (http://webs.iiitd.edu.in/raghava/cellppdmod/).

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“…Although their mechanism of entry inside the cells remains highly debated, they are still used to deliver numerous pharmaceutical molecules inside various types of cells. In our previous study [10], we have successfully shown cellular uptake as well as enhanced antifungal activity of TAT 2 conjugated Natamycin in human corneal epithelial cell line. Now to further test the antifungal efficacy in vivo, we have developed a murine model of fungal keratitis using clinical isolate of Fusarium dimerum.…”

Section: Introductionmentioning

confidence: 87%

Development of murine model of Fungal Keratitis to test the antifungal efficacy of CPP conjugated Natamycin

Rohira¹,

Shankar²,

Shah³

et al. 2018

Proceedings of the 35th European Peptide Symposium

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Corneal diseases including microbial keratitis are among the major causes of visual impairment and blindness worldwide. About 50% of the total microbial keratitis is caused by various fungal species. Fusarium and Aspergillus species are found to be the most common isolates in India. Natamycin is the only FDA approved drug which is used as a first line of treatment for fungal keratitis. Drawbacks associated with the use of natamycin is poor intraocular penetrationand poor water solubility. Cell penetrating peptides (CPPs) are positively charged short peptides that can translocate across the cell membrane without damaging the cell. In our study, one of the CPP i.e. TAT is used as a nanocarrier to deliver an antifungal compound, Natamycin inside the corneal cells. Recently, we have successfully shown the increased uptake of TAT dimer conjugated natamycin by corneal cells in vitro. Also, conjugated natamycin showed increased water solubility as well as antifungal activity in comparison to natamycin alone. To further investigate the antifungal activity of CPP conjugated natamycin (TAT 2-Natamycin) in vivo, we have developed a murine model of Fusarium keratitis. Immunocompromised female BALB/c mice were inoculated with different concentrationsof Fusarium sp. spores and were clinically graded (0 to 4 based on the severity of the disease) after three days of infection. Based on clinical grading and microbiological examination, 10 5 spores/5µl was found to be the optimum concentrationfor the establishment of fungal keratitis. We are currently testing TAT 2-Natamycin on this animal model for its antifungal activity and the results will be compared with the marketed formulation of natamycin (Natamycin 5% suspension).

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Cell Penetrating Peptides as Efficient Nanocarriers for Delivery of Antifungal Compound, Natamycin for the Treatment of Fungal Keratitis

Abstract: The formation of CPP-natamycin complex is clinically significant as it may enhance the bioavailability of natamycin in corneal tissues and aid in efficient management of fungal keratitis.

Cited by 38 publications

References 33 publications

Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens

Prediction of Cell-Penetrating Potential of Modified Peptides Containing Natural and Chemically Modified Residues

Development of murine model of Fungal Keratitis to test the antifungal efficacy of CPP conjugated Natamycin

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