Controlled Systemic Release of Therapeutic Peptides from PEGylated Prodrugs by Serum Proteases

Nollmann, Friederike I.; Goldbach, Tina; Berthold, Nicole; Hoffmann, Ralf

doi:10.1002/anie.201301533

Cited by 26 publications

(25 citation statements)

References 14 publications

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“…We therefore chose the option to protect the susceptible points of proteolysis of the molecule. Other options may increase the stability such as polyethyleneglycol (PEG) [31], the use of lipids for drug delivery of the peptides [32], the use of nanoparticules in order to achieve a longer life time [33] or the use of dendrimers [34]. The mastoparan family is a very promising group of potential new drugs.…”

Section: Resultsmentioning

confidence: 99%

Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii

Vila-Farrés

López-Rojas

Pachón-Ibáñez

et al. 2015

European Journal of Medicinal Chemistry

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The treatment of some infectious diseases can currently be very challenging since the spread of multi-, extended- or pan-resistant bacteria has considerably increased over time. On the other hand, the number of new antibiotics approved by the FDA has decreased drastically over the last 30 years. The main objective of this study was to investigate the activity of wasp peptides, specifically mastoparan and some of its derivatives against extended-resistant Acinetobacter baumannii. We optimized the stability of mastoparan in human serum since the specie obtained after the action of the enzymes present in human serum is not active. Thus, 10 derivatives of mastoparan were synthetized. Mastoparan analogues (guanidilated at the N-terminal, enantiomeric version and mastoparan with an extra positive charge at the C-terminal) showed the same activity against Acinetobacter baumannii as the original peptide (2.7 μM) and maintained their stability to more than 24 h in the presence of human serum compared to the original compound. The mechanism of action of all the peptides was carried out using a leakage assay. It was shown that mastoparan and the abovementioned analogues were those that released more carboxyfluorescein. In addition, the effect of mastoparan and its enantiomer against A. baumannii was studied using transmission electron microscopy (TEM). These results suggested that several analogues of mastoparan could be good candidates in the battle against highly resistant A. baumannii infections since they showed good activity and high stability.

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Section: Resultsmentioning

confidence: 99%

Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii

Vila-Farrés

López-Rojas

Pachón-Ibáñez

et al. 2015

European Journal of Medicinal Chemistry

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“…[4d, 16] Peptide masses were confirmed by MALDI-TOF-MS. Bacterial cultures (see the Supporting Information) were grown in lysogeny broth (LB) Miller (10 g L À1 NaCl) or 1 % (w/v) tryptic soy broth (TSB; 33 % TSB medium) at 37 8C under aerobic conditions. Antibacterial activities were determined in triplicate by a liquid broth microdilution assay in sterile 96-well plates with 33 % TSB medium (7.5 10 5 cells per well; 20 AE 2 h, 378C).…”

Section: Methodsmentioning

confidence: 99%

Insect‐Derived Proline‐Rich Antimicrobial Peptides Kill Bacteria by Inhibiting Bacterial Protein Translation at the 70 S Ribosome

et al. 2014

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Proline-rich antimicrobial peptides (PrAMPs) have been investigated and optimized by several research groups and companies as promising lead compounds to treat systemic infections caused by Gram-negative bacteria. PrAMPs, such as apidaecins and oncocins, enter the bacteria and kill them apparently through inhibition of specific targets without a lytic effect on the membranes. Both apidaecins and oncocins were shown to bind with nanomolar dissociation constants to the 70S ribosome. In apidaecins, at least the two C-terminal residues (Arg17 and Leu18) interact strongly with the 70S ribosome, whereas residues Lys3, Tyr6, Leu7, and Arg11 are the major interaction sites in oncocins. Oncocins inhibited protein biosynthesis very efficiently in vitro with half maximal inhibitory concentrations (IC50 values) of 150 to 240 nmol L(-1). The chaperone DnaK is most likely not the main target of PrAMPs but it binds them with lower affinity.

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“…Peptide-specific problems such as delivery [40,[79][80][81][82] and ADME profiles [83] can be often side-stepped by switching to an alternative route of administration [83] and employing techniques such as lipidization [84][85][86][87] and PEGylation [88][89][90], respectively. Medicinal chemistry is also used extensively to determine the pharmacophore of peptides.…”

Section: Role Of Medicinal Chemistry In Development Of Peptide-based mentioning

confidence: 99%

Cone Snail Venomics: From Novel Biology to Novel Therapeutics

et al. 2014

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Peptide neurotoxins from cone snails called conotoxins are renowned for their therapeutic potential to treat pain and several neurodegenerative diseases. Inefficient assay-guided discovery methods have been replaced by high-throughput bioassays integrated with advanced MS and next-generation sequencing, ushering in the era of 'venomics'. In this review, we focus on the impact of venomics on the understanding of cone snail biology as well as the application of venomics to accelerate the discovery of new conotoxins. We also discuss the continued importance of medicinal chemistry approaches to optimize conotoxins for clinical use, with a descriptive case study of MrIA featured.

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Controlled Systemic Release of Therapeutic Peptides from PEGylated Prodrugs by Serum Proteases

Cited by 26 publications

References 14 publications

Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii

Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii

Insect‐Derived Proline‐Rich Antimicrobial Peptides Kill Bacteria by Inhibiting Bacterial Protein Translation at the 70 S Ribosome

Cone Snail Venomics: From Novel Biology to Novel Therapeutics

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