A Systematic Structure–Activity Study of a New Type of Small Peptidic Transfection Vector Reveals the Importance of a Special Oxo‐Anion‐Binding Motif for Gene Delivery. (25th October 2017)

• Record Type: Journal Article
• Authors: Junghänel, Sandra; Karczewski, Sarah; Bäcker, Sandra; Knauer, Shirley K.; Schmuck, Carsten
• Is Part Of: Chembiochem. Volume 18:Number 22(2017)
• Page Start: 2268
• Page End: 2279
• Publication Date: 2017-10-25
• Subjects: DNA binding ligands -- gene transfection -- molecular recognition -- nonviral transfection vectors -- structure–activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700433
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: We discovered a new class of artificial peptidic transfection vectors based on an artificial anion‐binding motif, the guanidiniocarbonylpyrrole (GCP) cation. This new type of vector is surprisingly smaller than traditional systems, and our previous work suggested that the GCP group was important for promoting critical endosomal escape. We now present here a systematic comparison of similar DNA ligands featuring our GCP oxo‐anion‐binding motif with DNA ligands only consisting of naturally occurring amino acids. Structure–activity studies showed that the artificial binding motif clearly outperformed natural amino acids such as histidine, lysine, and arginine. It improved the ability to shuttle foreign genetic material into cells, yet successfully mediated endosomal escape. Also, plasmids that were complexed by our artificial ligands were stabilized against cytosolic degradation to some extent. This resulted in the successful expression of plasmid information (comparable to gold standards such as polyethyleneimine). Hence, our study clearly demonstrates the importance of the tailor‐made GCP anion‐binding site for efficient gene transfection. Abstract : Small cationic peptides are efficient gene‐transfection vectors, however, only if they contain a tailor‐made oxo‐anion binding site, the guanidiniocarbonylpyrrole (GCP) cation. Peptides with arginine, lysine, or histidine instead do not lead to gene transfection. The impact of the GCP cation is manifold: better binding to DNA, enhanced endosomal release, and cellular protection of DNA, among others.