Universität zu Köln

Grabeck, Joshua ORCID: 0000-0003-1126-1647, Luetzenburg, Tamara, Frommelt, Pia and Neundorf, Ines ORCID: 0000-0001-6450-3991 (2022). Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates. Molecules, 27 (19). BASEL: MDPI. ISSN 1420-3049

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Abstract

Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18(Delta E), which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18(Delta E) could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Grabeck, Joshua UNSPECIFIED orcid.org/0000-0003-1126-1647 UNSPECIFIED Luetzenburg, Tamara UNSPECIFIED UNSPECIFIED UNSPECIFIED Frommelt, Pia UNSPECIFIED UNSPECIFIED UNSPECIFIED Neundorf, Ines UNSPECIFIED orcid.org/0000-0001-6450-3991 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-656926
DOI:	10.3390/molecules27196656
Journal or Publication Title:	Molecules
Volume:	27
Number:	19
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1420-3049
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DELIVERY; SPHEROIDS; CANCER Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/65692