The medicinal chemistry of short lactoferricin-based antibacterial peptides.
ABSTRACT This review discusses antibacterial peptides from the perspective of development into clinically useful chemotherapeutic drugs using short lactoferricin based peptides as examples. The review shows how important features for antibacterial activity can be identified and explored using the molecular properties of a range of natural and non-natural amino acids. The results have been further refined quantitatively using a "soft-modelling" approach where important structural parameters that influence the antibacterial activity of 15-residue model peptides were identified. The review describes how this knowledge is utilised to generate pharmacophores for antibacterial efficacy. These pharmacophores turn out to be surprisingly small and relatively consistent between typical Gram-negative and Gram-positive bacteria leading to the discovery of a novel class of short synthetic cationic antimicrobial peptides. These compounds are found to have high antibacterial activity against several bacterial strains that are resistant to commercial antibiotics, and are promising as future clinical candidates for treatment of infections caused by several clinically relevant pathogens.
- SourceAvailable from: Ivana Cacciatore[show abstract] [hide abstract]
ABSTRACT: Worldwide efforts are underway to develop new antimicrobial agents against bacterial resistance. To identify new compounds with a good antimicrobial profile, we designed and synthesized two series of small cationic antimicrobial peptidomimetics (1-8) containing unusual arginine mimetics (to introduce cationic charges) and several aromatic amino acids (bulky moieties to improve lipophilicity). Both series were screened for in vitro antibacterial activity against a representative panel of Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacterial strains, and Candida albicans. The biological screening showed that peptidomimetics containing tryptophan residues are endowed with the best antimicrobial activity against S. aureus and S. epidermidis in respect to the other synthesized derivatives (MIC values range 7.5-50 µg/ml). Moreover, small antimicrobial peptidomimetics derivatives 2 and 5 showed an appreciable activity against the tested Gram-negative bacteria and C. albicans. The most active compounds (1-2 and 5-6) have been tested against Gram-positive established biofilm, too. Results showed that the biofilm inhibitory concentration values of these compounds were never up to 200 µg/ml. The replacement of tryptophan with phenylalanine or tyrosine resulted in considerable loss of the antibacterial action (compounds 3-4 and 7-8) against both Gram-positive and Gram-negative bacterial strains. Furthermore, by evaluating hemolytic activity, the synthesized compounds did not reveal cytotoxic activities, except for compound 5.Journal of Peptide Science 07/2012; 18(9):567-78. · 2.07 Impact Factor
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ABSTRACT: The cytotoxic activity of 10 analogs of the idealized amphipathic helical 21-mer peptide (KAAKKAA)3, where three of the Ala residues at different positions have been replaced with Trp residues, has been investigated. The peptide's cytotoxic activity was found to be markedly dependent upon the position of the Trp residues within the hydrophobic sector of an idealized α-helix. The peptides with Trp residues located opposite the cationic sector displayed no antitumor activity, whereas those peptides with two or three Trp residues located adjacent to the cationic sector exhibited high cytotoxic activity when tested against three different cancer cell lines. Dye release experiments revealed that in contrast to the peptides with Trp residues located opposite the cationic sector, the peptides with Trp residues located adjacent to the cationic sector induced a strong permeabilizing activity from liposomes composed of a mixture of zwitterionic phosphatidylcholine and negatively charged phosphatidylserine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS)) (2:1) but not from liposomes composed of zwitterionic phosphatidylcholine, POPC. Fluorescence blue shift and quenching experiments revealed that Trp residues inserted deeper into the hydrophobic environment of POPC/POPS liposomes for peptides with high cytotoxic activity. Through circular dichroism studies, a correlation between the cytotoxic activity and the α-helical propensity was established. Structural studies of one inactive and two active peptides in the presence of micelles using NMR spectroscopy showed that only the active peptides adopted highly coiled to helical structures when bound to a membrane surface.Journal of Biological Chemistry 11/2011; 287(1):233-44. · 4.65 Impact Factor
Article: Lactoferrin, a bird's eye view.[show abstract] [hide abstract]
ABSTRACT: Lactoferrin is an abundant iron-binding protein in milk. This 80 kDa bilobal glycoprotein is also present in several other secreted bodily fluids, as well as in the secondary granules of neutrophils. The potent iron-binding properties of lactoferrin can locally create iron deficiency, and this is an important factor in host defense as it prevents bacteria from growing and forming biofilms. In addition to having antibacterial activity, lactoferrin is now known to have a long list of other beneficial biological properties. It has direct antiviral, antifungal, and even some anticancer activities. It can also promote wound healing and bone growth, or it can act as an iron carrier. Moreover, lactoferrin displays a cytokine-like "alarmin" activity, and it activates the immune system. Simultaneously, it can bind endotoxin (lipopolysaccharide), and in doing so, it modulates the activity of the host immune response. The majority of these intriguing biological activities reside in the unique positively charged N-terminal region of the protein. Interestingly, several peptides, which retain many of the beneficial activities, can be released from this region of lactoferrin. An isoform of the human protein, known as delta-lactoferrin, is expressed inside many cells, where it acts as a transcription factor. Lactoferrin purified from human and bovine milk have very similar but not completely identical properties. Lactoferrin receptors have been identified on the surface of various cells, and some of these can bind both the human and the bovine protein. Because of the extensive health-promoting effects of lactoferrin, there has been considerable interest in the use of bovine or human lactoferrin as a "protein nutraceutical" or as a therapeutic protein. When lactoferrin is used as a "biologic drug", it seems to be orally active in contrast to most other therapeutic proteins.Biochemistry and Cell Biology 04/2012; 90(3):233-44. · 2.92 Impact Factor