Guanidinium compounds imitating the bis(arginine) structural motif of staphylococcal nuclease (e.g. 3) are known to be powerful catalysts for phosphoryl transfer reactions in dipolar aprotic solvents. Compound 3 also accelerates the hydrolysis of RNA (H,O, pH 7). However, due to diminished substrate affinity in H,O, the rate effects are less pronounced in aqueous than in aprotic solution. To test if a synthetic ribonuclease may be derived from the bis(guanidinium) moiety of 3 by the addition of RNA-binding substructures, the TAR sequence of HIV-1 was chosen as a target. The arginine residue ofcompound 4 serves as an extremely simplified mimic of tat, a protein responsible for boosting the viral transcription by complex formation with TAR. Here, we present the synthesis of 4 and its ability to bind and to cleave efficiently the truncated TAR sequence 1. In addition, the synthesis of an acridine arginine conjugate, 19, is reported in preliminary form. Compound 19 associates with 1 and completely blocks the cleavage induced by 4.

Detailed knowledge of enzyme mechanisms has previously led to the design of „enzyme mimetics”︁, small synthetic compounds that use the same principles of catalysis as enzymes but need a less complicated framework than proteins. The development of enzyme mimetics for the hydrolysis of RNA is of special interest because of their potential use as drugs in gene therapy. Field development from the first active compounds discovered in the late 80s to the application of highly specific artificial RNases in vitro is described.

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Detailliertes Wissen uber den Wirkmechanismus von Enzymen hat dazu gefuhrt, dai3 deren Katalyseprinzipien auf weniger komplexe synthetische Molekule ubertragen werden konnen. Die Entwicklung von Enzymrnodellen fur die Hydrolyse von RNA ist von besonderer Bedeutung, da sie potentiell als Medikamente in der Gentherapie eingesetzt werden konnen. Der Weg von den ersten aktiven Verbindun-Fur lhre Dokumentation von Nr. 2/98 Chemie in unserer Zeit