Protein Design: Template‐Assembled Synthetic Proteins

Carey, Robert I.; Altmann, Karl‐Heinz; Mutter, Manfred

doi:10.1002/9780470514085.ch13

Cited by 2 publications

(1 citation statement)

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“…We then translated this system into a more defined one by using a cyclodecapeptide as the building block of the conjugate. This template has a constrained planar structure due to its amino acidic structure, creating two specific reactive domains that qualify for multiple side modifications [17][18][19]. The defined structure of the cyclodecapeptide allows precise targeting of the position and number of PS moieties to load, resulting in strictly shaped final prodrugs.…”

Section: Introductionmentioning

confidence: 99%

Double-PEGylated Cyclopeptidic Photosensitizer Prodrug Improves Drug Uptake from In Vitro to Hen’s Egg Chorioallantoic Membrane Model

et al. 2021

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Cyclopeptidic photosensitizer prodrugs (cPPPs) are compounds designed to specifically target overexpressed hydrolases such as serine proteases, resulting in their specific activation in close proximity to tumor cells. In this study, we explored a series of conjugates that can be selectively activated by the urokinase plasminogen activator (uPA). They differ from each other by their pheophorbide a (Pha) loading, their number of PEG chains and the eventual presence of black hole quenchers (BHQ3). The involvement of a peptidic linker between the drugs and the cyclopeptidic carrier allows specific cleavage by uPA. Restoration of the photophysical activity was observed in vitro on A549 lung and MCF7 breast cancer cells that exhibited an increase in red fluorescence emission up to 5.1-fold and 7.8-fold, respectively for uPA-cPPQ2+2/5. While these cPPP conjugates do not show dark toxicity, they revealed their phototoxic potential in both cell lines at 5 µM of Phaeq and a blue light fluence of 12.7 J/cm2 that resulted in complete cell death with almost all conjugates. This suggests, in addition to the promising use for cancer diagnosis, a use as a PDT agent. Intravenous injection of tetrasubstituted conjugates in fertilized hen eggs bearing a lung cancer nodule (A549) showed that a double PEGylation was favorable for the selective accumulation of the unquenched Pha moieties in the tumor nodules. Indeed, the diPEGylated uPA-cPPP4/52 induced a 5.2-fold increase in fluorescence, while the monoPEGylated uPA-cPPP4/5 or uPA-cPPQ2+2/5 led to a 0.4-fold increase only.

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Section: Introductionmentioning

confidence: 99%