RNA‐Aminoglycosid‐Wechselwirkungen: Design und Synthese von „Amino‐aminoglycosiden”︁ und deren Bindung an RNA

Abstract

Die elektrostatische Wechselwirkung ist entscheidend bei der Bindung von Aminoglycosid‐Antibiotica an RNA. Dies ergab der Austausch von OH‐ gegen NH2‐Gruppen, z.B. in Kanamycin A 1. Das Derivat 2 inhibiert ein Hammerhead‐Ribozym viel stärker als 1. Es wird vorgeschlagen, daß die räumliche Anordnung der positiven Ladungen die Bindungsstärke der Aminoglycoside bestimmt.

Strategies for the Design of Drugs Targeting RNA and RNA–Protein Complexes

“…Experimental studies on hammerhead RNA ± drug complexes containing designed aminoglycoside derivatives in which the number, the basicity, or the flexibility of the attachment of ammonium groups has been systematically altered [30,128,192] support the model of structural electrostatic complementarity. [34] When either the number or the charge density of ammonium groups in aminoglycosides is increased, the inhibitory activity of the compounds is enhanced.…”

“…They can govern, however, specific recognition in the binding of conformationally constrained polycationic molecules to RNA folds as revealed by investigations on the interaction of aminoglycosides with different RNA targets. [30,34,128,129,192] In a quantitative approach using surface plasmon resonance, it has been demonstrated that increasing the ionic competition by adding salt to RNA ± aminoglycoside complexes decreased both the specific and nonspecific drug binding to about the same extent. [128] In other words, the electrostatic component of the binding energy contributed, as expected, to the unspecific binding but also, to a remarkable extent, to the specific binding.…”

“…[34] When either the number or the charge density of ammonium groups in aminoglycosides is increased, the inhibitory activity of the compounds is enhanced. [30,34,192] The binding specificity of aminoglycosides is diminished when the conformational constraint on the aminoglycoside scaffold is partially relieved by replacing one of the ring substructures by a more flexible aliphatic chain carrying one or more amine groups (Compounds 3 and 4 in Figure 3). [128] The concept of structural electrostatic complementarity has been successfully used to explain the structural basis of aminoglycoside inhibition of self-splicing group I introns.…”

Designing Novel RNA Binders

“…[23] We have demonstrated that substituting a hydroxyl with an amino group can convert a very poor RNA binder, such as kanamycin A, to a reasonably strong one. Thus, 6''-amino-6''-deoxykanamycin A is as effective as kanamycin B, a natural product containing five amino groups.…”

“…Tobramycin binds a number of natural RNAs with higher affinity than kanamycin B (Figure 1), [12,18,23] although both compounds contain five amino groups. The only difference between the two antibiotics is an additional hydroxyl group at the 3'-position in kanamycin B.…”