Simple methods of in vivo testing for peripheral M- and D-antagonists of serotonin

Rogova, L.S.

doi:10.1007/bf00803469

Cited by 1 publication

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“…Oncocins, including Onc72 (VDKPPYLPRPRPPROIYNO‐NH 2 ) and Onc112, diffuse passively across the outer membrane of Gram‐negative bacteria before they are taken up by SbmA and MdtM inner membrane transporter systems to enter the cytoplasm and inhibit protein translation by blocking the 70S ribosome exit tunnel and destabilizing the initiation complex. [ 21,22 ] Onc72 is highly active against several Gram‐negative human pathogens, such as Escherichia coli , Klebsiella pneumoniae , and Acinetobacter baumannii , and is very slowly degraded by proteases. [ 23,24 ] Importantly, the high efficacy and pharmaceutical promise of Onc72 have been confirmed in different murine infection models, [ 25 ] including a multiresistant, KPC‐producing K. pneumoniae strain in a murine septicemia model and a murine thigh infection model using an antibiotic‐susceptible K. pneumoniae strain, despite fast renal clearance rates.…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%