Pharmacokinetics and<i>in vivo</i>efficacy of optimized oncocin derivatives

Schmidt, Rico; Ostorházi, Eszter; Wende, Elisabeth; Knappe, Daniel; Hoffmann, Ralf

doi:10.1093/jac/dkv454

Cited by 29 publications

(42 citation statements)

References 23 publications

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“…The strong accumulation in kidneys and renal excretion was expected for the short polar peptides, as already noted for oncocin derivatives (Holfeld et al, 2015; Schmidt et al, 2016). Therefore, the tissue distribution was further investigated using homogenates of kidney, liver, and brain besides the appearance in urine.…”

Section: Resultssupporting

confidence: 60%

“…Both peptides and their two major metabolites were studied in blood, urine, and homogenates of kidney, liver, and brain. Together with previous reports on the pharmacokinetics and in vivo efficacy of Onc72 and Onc112 (Knappe et al, 2012; Holfeld et al, 2015; Schmidt et al, 2016) the results presented here for Api88 and Api137 provide the first comprehensive representation of the therapeutic potential of insect-derived PrAMPs.…”

Section: Introductionsupporting

confidence: 74%

“…A sensitive RP-HPLC-ESI-MS approach for targeted quantification of Api88, Api137, and their identical metabolites containing the N-terminal 16 (Api1-16) or 17 residues (Api1-17) was developed based on a protocol recently reported for oncocins (Schmidt et al, 2016). The MRM relied on triply protonated precursor ions and a neutral loss of two molecules of dimethylamine from the N-terminal N , N , N ′, N ′-tetramethylguanidine group, which was highly selective and sensitive providing limits of quantification (LOQ) from 19 to 59 ng/mL (~9 to ~25 nmol/L).…”

Section: Resultsmentioning

confidence: 99%

“…A protocol to quantify Api88, Api137, and their major metabolites was established analog to that of oncocin derivatives, reported recently (Schmidt et al, 2016). Briefly, an Alliance® 2695 HPLC system was coupled online to an ESI-QqLIT-MS (4,000 QTRAP®) equipped with a TurboV™ ion-spray source and operated in positive ion MRM mode using the Analyst® 1.6 software.…”

Section: Methodsmentioning

confidence: 99%

“…For example, the diabetes peptide drugs exenatide and pramlintide are given at daily doses of 20 μg (Byetta®; ~0.5 μg/kg) and 120 μg (Symlin®; ~1.5 μg/kg; Heine et al, 2005; Hay et al, 2015), while antimicrobial peptides are usually administered at 50- to 100-fold higher doses (>5 mg/kg) in order to achieve high in vivo efficacies (Benincasa et al, 2010; Szabo et al, 2010; Brunetti et al, 2016). This is also true for proline-rich AMPs (PrAMPs), such as insect-derived oncocin and apidaecin analogs that showed protective effects in murine intraperitoneal and intramuscular infections with Escherichia coli ATCC 25922 and antibiotic-susceptible and -resistant Klebsiella pneumoniae strains (Czihal et al, 2012; Knappe et al, 2012, 2015; Ostorhazi et al, 2014; Schmidt et al, 2016). Mechanistically, cationic AMPs first electrostatically interact with the negatively charged surface of bacteria and—depending on the secondary structure—act on the membrane or reach the periplasmic space possibly by spontaneous translocation (Hancock, 1997; Brogden, 2005; Scocchi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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In vivo Efficacy and Pharmacokinetics of Optimized Apidaecin Analogs

et al. 2017

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Proline-rich antimicrobial peptides (PrAMPs) represent promising alternative therapeutic options for the treatment of multidrug-resistant bacterial infections. PrAMPs are predominantly active against Gram-negative bacteria by inhibiting protein expression via at least two different modes of action, i.e., blocking the ribosomal exit tunnel of 70S ribosomes (oncocin-type binding) or inhibiting the assembly of the 50S ribosomal subunit (apidaecin-type binding). The in vivo efficacy and favorable biodistribution of oncocins confirmed the therapeutic potential of short PrAMPs for the first time, whereas the in vivo evaluation of apidaecins is still limited despite the promising efficacy of apidaecin-analog Api88 in an intraperitoneal murine infection model. Here, the in vivo efficacy of apidaecin-analog Api137 was studied, which rescued all NMRI mice from a lethal intraperitoneal infection with E. coli ATCC 25922 when administered three times intraperitoneal at doses of 0.6 mg/kg starting 1 h after infection. When Api88 and Api137 were administered intravenous or intraperitoneal at doses of 5 and 20 mg/kg, their plasma levels were similarly low (<3 μg/mL) and four-fold lower than for oncocin-analog Onc72. This contradicted earlier expectation based on the very low serum stability of Api88 with a half-life time of only ~5 min compared to ~6 and ~3 h for Api137 and Onc72, respectively. Pharmacokinetic data relying on a sensitive mass spectrometry method utilizing multiple reaction monitoring and isotope-labeled peptides revealed that Api88 and Api137 were present in blood, urine, and kidney, and liver homogenates at similar levels accompanied by the same major metabolites comprising residues 1–16 and 1–17. The pretended discrepancy was solved, when all peptides were incubated in peritoneal lavage. Api137 was rapidly degraded at the C-terminus, while Api88 was rather stable despite releasing the same degradation products. Onc72 was very stable explaining its higher plasma levels compared to Api88 and Api137 after intraperitoneal administration illuminating its good in vivo efficacy. The data indicate that the degradation of therapeutic peptides should be studied in serum and further body fluids. Moreover, the high efficacy in murine infection models and the fast clearance of Api88 and Api137 within ~60 min after intravenous and ~90 min after intraperitoneal injections indicate that their in vivo efficacy relates to the maximal peptide concentration achieved in blood.

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Section: Resultssupporting

confidence: 60%

Section: Introductionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo Efficacy and Pharmacokinetics of Optimized Apidaecin Analogs

et al. 2017

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In Vitro Properties and Pharmacokinetics of Temporarily PEGylated Onc72 Prodrugs

Mohammed

Böttger

Krizsan

et al. 2023

Adv Healthcare Materials

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The favorable properties of antimicrobial peptides (AMPs) to rapidly kill pathogens are often limited by unfavorable pharmacokinetics due to fast degradation and renal clearance rates. Here, a prodrug strategy linking proline‐rich AMP Onc72 to polyethylene glycol (PEGs) with average molecular weights of 5 and 20 kDa via a peptide linker containing a protease cleavage site is tested for the first time in vivo. Onc72 is released from these 5k‐ and 20k‐prodrugs in mouse serum with half‐life times (t1/2) of 8 and 14 h, respectively. Importantly, PEGylation protects Onc72 from proteolytic degradation providing a prolonged release of Onc72, balancing the degradation of free Onc72, and leading to relatively stable Onc72 concentrations and high antibacterial activities. The prodrugs are not hemolytic on human erythrocytes and show only slight cytotoxic effects on human cell lines indicating promising safety margins. When administered subcutaneously to female CD‐1 mice, the prodrugs elimination t1/2 are 66 min and ≈5.5 h, respectively, compared to 43 min of free Onc72. The maximal Onc72 plasma levels are obtained ≈1 and ≈8 h postadministration, respectively. In conclusion, the prodrugs provide extended elimination t1/2 and a constant release of Onc72 in mice, potentially limiting adverse effects and increasing efficacy.

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Ribosomal Target‐Binding Sites of Antimicrobial Peptides Api137 and Onc112 Are Conserved among Pathogens Indicating New Lead Structures To Develop Novel Broad‐Spectrum Antibiotics

Kolano¹,

Knappe²,

Volke³

et al. 2020

ChemBioChem

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Proline‐rich antimicrobial peptides expressed in insects are primarily active against Enterobacteriaceae. Mechanistically, they target the bacterial (70S) ribosome after partially transporter‐based cellular uptake, as revealed for Api137 and Onc112 on Escherichia coli. Following molecular modeling indicating that the Onc112 contact site is conserved among the ribosomes of high‐priority pathogens, the ribosome binding of Api137 and Onc112 was studied. The dissociation constants (Kd) of Onc112 were ∼75 nmol/L for Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, 36 nmol/L for Pseudomonas aeruginosa, and 102 nmol/L for Staphylococcus aureus, thus indicating a very promising lead structure for developing broad‐spectrum antibiotics. Api137 bound weaker with Kd values ranging from 155 nmol/L to 13 μmol/L. For most bacteria, the antibacterial activities were lower than predicted from the Kd values, which was only partially explained by their ability to enter bacterial cells. Other factors limiting the activity expected from the ribosome binding might be off‐target binding.

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Pharmacokinetics andin vivoefficacy of optimized oncocin derivatives

Cited by 29 publications

References 23 publications

In vivo Efficacy and Pharmacokinetics of Optimized Apidaecin Analogs

In vivo Efficacy and Pharmacokinetics of Optimized Apidaecin Analogs

In Vitro Properties and Pharmacokinetics of Temporarily PEGylated Onc72 Prodrugs

Ribosomal Target‐Binding Sites of Antimicrobial Peptides Api137 and Onc112 Are Conserved among Pathogens Indicating New Lead Structures To Develop Novel Broad‐Spectrum Antibiotics

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