Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

Abstract

We present here a new set of aminoglycoside-arginine conjugates (AACs) that are either site-specific or per-arginine conjugates of paromomycin, neamine, and neomycin B as well as their structure-activity relationships. Their binding constants (K D ) for TAR and RRE RNAs, measured by fluorescence anisotropy, revealed dependence on the number and location of arginines in the different aminoglycoside conjugates. The binding affinity of the per-arginine aminoglycosides to TAR is higher than to RRE, and hexa-arginine neomycin B is the most potent binder (K D = 5 and 23 nM, respectively). The 2D TOCSY NMR spectrum of the TAR monoarginine-neomycin complex reveals binding at the bulge region of TAR.

The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition

“…[7][8][9][10][11][12] In addition, these molecules specifically interact with several other RNA receptors, including t-RNA, aptamers, or the viral TAR sequence. [13][14][15][16] Finally, they are recognized by the enzymes involved in the drug inactivation that play a central role in bacterial resistance processes. 17 The 3-D structures of several antibiotic/RNA and antibiotic/protein complexes have been described in recent years by X-ray and NMR methods, 7-15,18-20 providing valuable information for the design of new aminoglycoside derivatives.…”

Biosynthesis of 2-Deoxystreptamine by Three Crucial Enzymes in Streptomyces fradiae NBRC 12773

“…It has been shown that aminoglycosides specifically bind to the bacterial ribosomal RNA and inhibit the bacterial protein biosynthesis [1]. Based on the specific interaction with RNA molecules, many applications such as anti-HIV infection [2,3] and anti-plasmid [4,5], are continuously investigated [6ϳ8]. Thus, the creation of a library for structurally diverse aminoglycoside molecules is strongly desired.…”

Biosynthesis of 2-Deoxystreptamine-containing Antibiotics in Streptoalloteichus hindustanus JCM 3268: Characterization of 2-Deoxy-scyllo-inosose Synthase

“…Keywords 2-deoxystreptamine biosynthetic genes, Streptoalloteichus hindustanus, 2-deoxy-scyllo-inosose synthase, kinetics Aminoglycosides are an important group of antibiotics in clinical use for a long time. Even today, new activities of aminoglycosides are being discovered; for example, the activity of arginine complexes against HIV [1,2]. Aminoglycosides are structurally oligosaccharides containing one of a small number of specific aminocyclitols and various amino sugars, which are connected together through the glycosidic bonds.…”