Design and recognition of cucurbituril-secured platinum-bound oligopeptides.
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ABSTRACT:
SUBMITTER: Barbero H
PROVIDER: S-EPMC8317623 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We designed and synthesized helical short oligopeptides with an L-proline on the N-terminus and hydrocarbon stapling on the side chain. Side-chain stapling is a frequently used method for the development of biologically active peptides. Side-chain stapling can stabilize the secondary structures of peptides, and, therefore, stapled peptides may be applicable to peptide-based organocatalysts. Olefin-tethered cis-4-hydroxy-L-proline 1 and L-serine 2 and 8, and (R)-?-allyl-proline 18 were used as cross-linking motifs and incorporated into helical peptide sequences. The Z- and E-selectivities were observed for the ring-closing metathesis reactions of peptides 3 and 11 (i,i+1 series), respectively, while no E/Z-selectivity was observed for that of 19 (i,i+3 series). The stapled peptide B' catalyzed the Michael addition reaction of 1-methylindole to ?,?-unsaturated aldehyde, which was seven times faster than that of unstapled peptide B. Furthermore, the high catalytic activity was retained even at lower catalyst loadings (5 mol %) and lower temperatures (0 °C). The circular dichroism spectra of stapled peptide B' showed a right-handed helix with a higher intensity than that of unstapled peptide B. These results indicate that the introduction of side-chain stapling is beneficial for enhancing the catalytic activity of short oligopeptide catalysts.
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Project description:BackgroundActivated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis.MethodsA kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice.ResultsThe 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects.ConclusionMultikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.
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Project description:Poly(ADP-ribose) polymerase-1 (PARP-1) was recently identified as a platinum-DNA damage response protein. To investigate the properties of binding of PARP-1 to different platinum-DNA adducts in greater detail, biotinylated DNA probes containing a site-specific cisplatin 1,2-d(GpG) or 1,3-d(GpTpG) intrastrand cross-link or a cisplatin 5'-GC/5'-GC interstrand cross-link (ICL) were utilized in binding assays with cell-free extracts (CFEs) in vitro. The activated state of PARP-1 was generated by treatment of cells with a DNA-damaging agent or by addition of NAD(+) to CFEs. PARP-1 binds with a higher affinity to cisplatin-damaged DNA than to undamaged DNA, and the amount of protein that binds to the most common cisplatin-DNA cross-link, 1,2-d(GpG), is greater than the amount that binds to other types of cisplatin-DNA cross-links. Both DNA damage-activated PARP-1 and unactivated PARP-1 bind to cisplatin-damaged DNA, and both automodified PARP-1 and cleaved PARP-1 bind to cisplatin-DNA lesions. The role of poly(ADP-ribose) (pADPr) in mediating binding of PARP-1 to platinum damage was further investigated. The extent of binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link decreases upon automodification, and overactivated PARP-1 loses its affinity for the cross-link. Elimination of pADPr facilitates binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link. PARP-1 also binds to DNA damaged by other platinum compounds, including oxaliplatin and pyriplatin, indicating protein affinity for the damage in an adduct-specific manner rather than recognition of distorted DNA. Our results reveal the unique binding properties for binding of PARP-1 to platinum-DNA damage, providing insights into, and a better understanding of, the cellular response to platinum-based anticancer drugs.
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