Falciani C.,University of Siena |
Lozzi L.,University of Siena |
Pollini S.,University of Siena |
Luca V.,University of Rome La Sapienza |
And 10 more authors.
PLoS ONE | Year: 2012
The branched M33 antimicrobial peptide was previously shown to be very active against Gram-negative bacterial pathogens, including multidrug-resistant strains. In an attempt to produce back-up molecules, we synthesized an M33 peptide isomer consisting of D-aminoacids (M33-D). This isomeric version showed 4 to 16-fold higher activity against Gram-positive pathogens, including Staphylococcus aureus and Staphylococcus epidermidis, than the original peptide, while retaining strong activity against Gram-negative bacteria. The antimicrobial activity of both peptides was influenced by their differential sensitivity to bacterial proteases. The better activity shown by M33-D against S. aureus compared to M33-L was confirmed in biofilm eradication experiments where M33-L showed 12% activity with respect to M33-D, and in vivo models where Balb-c mice infected with S. aureus showed 100% and 0% survival when treated with M33-D and M33-L, respectively. M33-D appears to be an interesting candidate for the development of novel broad-spectrum antimicrobials active against bacterial pathogens of clinical importance. © 2012 Falciani et al.
Falciani C.,University of Siena |
Falciani C.,SetLance Srl |
Lozzi L.,University of Siena |
Scali S.,University of Siena |
And 3 more authors.
Amino Acids | Year: 2014
M33 is a branched peptide currently under preclinical characterization for the development of a new antibacterial drug against gram-negative bacteria. Here, we report its pegylation at the C-terminus of the three-lysine-branching core and the resulting increase in stability to Pseudomonas aeruginosa elastase. This protease is a virulence factor that acts by destroying peptides of the native immune system. Peptide resistance to this protease is an important feature for M33-Peg activity against Pseudomonas. © 2014 Springer-Verlag Wien.
Setlance S.r.L. | Date: 2012-01-25
The instant invention refers to an antibacterial peptide with all aminoacids in D configuration, possessing strong antimicrobial activity against Gram-negative and Gram-positive bacteria and Candida strains. The peptide can be in linear form or multimerised on a skeleton of polyacrylamide, of dextrane units or on a skeleton of ethylene glycol units. The peptide is resistant to proteolysis mainly when synthesized in the tetra-branched form where identical peptide sequences are linked together by an appropriate molecular scaffold.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: NMP.2013.1.2-2 | Award Amount: 7.53M | Year: 2014
The main objective of PneumoNP is the development of a theragnostic system for the treatment of lung Gram-negative bacterial infections. As a proof of concept PneumoNP will focus the attention on Klebsiella pneumoniae caused infections. A diagnostic kit will be developed to enable a rapid and precise identification of the bacteria strain causing the infection and avoid the use of wide spectrum antibiotics. For the treatment a nanotherapeutic based inhalable antibiotic will be developed. The therapeutic nanosystem will be based on a nanocarrier combined with an antimicrobial peptide. 3 different types of NCs will be tested with 2 AMPs to be able to obtain a novel effective inhalable antimicrobial NS. Nanotherapeutics offers many advantages in pulmonary drug-delivery, due to the huge surface area available in the lungs and their potential to achieve uniform distribution of drug dose among the alveoli. To improve this delivery to the lungs an aerosol system will also be developed. Due to the characteristics related to pulmonary delivery of NCs, topical and systemic bioavailabilities are envisaged. A diagnostic kit will be generated to monitor the efficacy and efficiency of the therapy. Once this treatment is proved to be effective, it could then be applied to any Gram-negative lung bacterial infection. The number of antibiotic resistant bacteria strains is increasing rapidly, new types of therapy are urgently required to avoid the use of standard antibiotics. Gram-negative bacteria that cause pneumonia are one of the main sources of nosocomial infections, mainly in people with a weakened immune system. Apart from pneumonia they can cause bacteremia and other infections. Early detection of the infection source combined with the development of appropriate and effective NSs to treat multi-drug resistant (MDR) bacteria caused infections will definitely radically improve the healing process of patients and avoid complications for people in hospital.
Setlance S.R.L. | Date: 2011-07-11
The instant invention refers to an antibacterial peptide with all aminoacids in D-configuration, possessing strong antimicrobial activity against Gram-negative and Gram-positive bacteria and Candida strains. The peptide can be in linear form or multimerised on a skeleton of polyacrylamide, of dextrane units or on a skeleton of ethylene glycol units. The peptide is resistant to proteolysis especially when synthesized in the tetra-branched form where identical peptide sequences are linked together by an appropriate molecular scaffold.
PubMed | SetLance srl, CIC Biomagune, University of Florence and University of Siena
Type: | Journal: Scientific reports | Year: 2016
A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5M and 3M for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years.
PubMed | SetLance srl, University of Florence and University of Siena
Type: | Journal: Scientific reports | Year: 2015
Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity.
PubMed | Setlance srl
Type: | Journal: Current topics in medicinal chemistry | Year: 2016
The increasing frequency of multi-resistant Gram-positive and Gram-negative bacteria and a long-term decreasing trend in the development of new antimicrobial molecules prompts research for new anti-infective agents with new modes of action. Antimicrobial peptides (AMPs) are considered an interesting class of antibacterial molecules. Many new AMPs have been discovered and some are being evaluated for the development of new antibacterial therapeutics. Since the development of new antibacterial drugs has been neglected for decades, we are now facing with extreme medical need combined with a lack of technical experimental progress in setting up efficient models of antibacterial activity in animals. Here we review experiments with AMPs in animal models of sepsis, pneumonia and skin infection caused by bacteria. Animal models of infection have been of enormous predictive value in antibacterial drug discovery, both for elucidating AMP efficacy in the treatment of experimentally induced infection and for comparing the effectiveness of two or more antibiotics.
PubMed | SetLance srl and University of Siena
Type: | Journal: Scientific reports | Year: 2016
The tetra-branched peptide NT4 selectively binds to different human cancer cells and tissues. NT4 specifically binds to sulfated glycosaminoglycans on cancer cell membranes. Since sulfated glycosaminoglycans are involved in cancer cell interaction with the extracellular matrix, we evaluated the effect of NT4 on cancer cell adhesion and migration. We demonstrated here that the branched peptide NT4 binds sulfated glycosaminoglycans with high affinity and with preferential binding to heparan sulfate. NT4 inhibits cancer cell adhesion and migration on different proteins, without modifying cancer cell morphology or their ability to produce protrusions, but dramatically affecting the directionality and polarity of cell movement. Results obtained by taking advantage of the selective targeting of glycosaminoglycans chains by NT4, provide insights into the role of heparan sulfate proteoglycans in cancer cell adhesion and migration and suggest a determinant role of sulfated glycosaminoglycans in the control of cancer cell directional migration.
PubMed | SetLance srl, University of Ferrara and University of Siena
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2016
The synthetic antimicrobial peptide SET-M33 has strong activity against bacterial infections caused by Gram-negative bacteria. It is currently in preclinical development as a new drug to treat lung infections caused by Gram-negative bacteria. Here we report its strong anti-inflammatory activity in terms of reduced expression of a number of cytokines, enzymes, and signal transduction factors involved in inflammation triggered by LPS from Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli Sixteen cytokines and other major agents involved in inflammation were analyzed in macrophages and bronchial cells after stimulation with LPS and incubation with SET-M33. The bronchial cells were obtained from a cystic fibrosis patient. A number of these proteins showed up to 100% reduction in expression as measured by RT-PCR, Western blotting, or Luminex technology. LPS neutralization was also demonstrated in vivo by challenging bronchoalveolar lavage of SET-M33-treated mice with LPS, which led to a sharp reduction in TNF- with respect to non-SET-M33-treated animals. We also describe a strong activity of SET-M33 in stimulating cell migration of keratinocytes in wound healing experiments in vitro, demonstrating a powerful immunomodulatory action generally characteristic of molecules taking part in innate immunity.