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Biomedical subjects

Hans-Dieter Arndt

Publications and source records attributed to Hans-Dieter Arndt.

7 recordsLinked to original sources
PubMed2005

Temperature-sensitive protein-DNA dimerizers.

Programmable DNA-binding polyamides coupled to short peptides have led to the creation of synthetic artificial transcription factors. A hairpin polyamide-YPWM tetrapeptide conjugate facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. Such small molecules function as protein-DNA dimerizers that stabilize complexes at composite DNA binding sites. Here we investigate the role of the linker that connects the polyamide to the peptide. We find that a substantial degree of variability in the linker length is tolerated at lower temperatures. At physiological temperatures, the longest linker tested confers a "switch"-like property on the protein-DNA dimerizer, in that it abolishes the ability of the YPWM moiety to recruit the natural transcription factor to DNA. These observations provide design principles for future artificial transcription factors that can be externally regulated and can function in concert with the cellular regulatory circuitry.

Amino Acid Sequence↗
PubMed2004

Small molecule transcription factor mimic.

Regulation of gene expression by transcription factors touches many aspects of eukaryotic biology, and its systematic, external control by organic molecules represents a challenge in chemistry. Here we report the design of a completely organic, nonpeptidic compound that mimics a transcription factor. The design takes advantage of the specific DNA-binding affinity of a hairpin polyamide molecule and the ability of wrenchnolol to bind to the Sur-2 subunit of human mediator complex. The hybrid compound of these two molecules activates transcription of a reporter gene in vitro in a promoter-dependent manner through simultaneous contacts with DNA and Sur-2. Our results indicate that it is possible to generate a transcription factor out of nonpeptidic components.

Adamantane↗
PubMed2004

Folding propensity of cyclohexylether-delta-peptides.

[structure: see text] Linear (n = 2-18) and cyclic oligomers (n = 3-8) of a cyclohexylether-delta-amino acid (COA) were prepared in high yield and stereopurity. CD spectra of the linear oligomers were indicative of secondary structure formation. X-ray crystal structures of cyclic COA oligomers revealed hydrophobic packing and internal 5- and 10-membered-ring hydrogen bonds. Ether and amide oxygens reside preferably in an ap orientation. This conformational locking is apparently broken by a C-2 substituent in an asymmetric cyclotrimer, for which a zeolithe-like tubular structure was found.

Amino Acids↗
PubMed2004

Stereoselective synthesis of trans-threo-trans-oligopyrrolidines: potential agents for RNA cleavage.

The 2,5-trans-substituted oligopyrrolidines constitute a promising class of novel RNA-binding agents as well as potential building blocks for artificial anion channels. A convergent synthesis of terpyrrolidine 1 and pyrrolidino-THF-pyrrolidine 2 is reported, relying upon convergent coupling of 2,5-trans-pyrrolidinecarboxaldehydes through bridging alkyne units under Felkin-Anh control and subsequent closure of the central ring. After complete deprotection, the free polyamine products were isolated in excellent yield and purity. Crystal structure analyses of a terpyrrolidine and a pyrrolidino-THF-pyrrolidine documented their helical privileged conformations. The compounds were then screened for RNA cleavage activity. Unlike the only weakly active simple polyamines, p-nitrosulfonamide 33 was found to induce cleavage at mM concentrations under physiologically relevant conditions.

Crystallization↗
PubMed2003

Toward artificial developmental regulators.

A polyamide-peptide conjugate is designed which recruits sequence specifically the developmental regulator Exd to a cognate DNA site. In particular, an eight-ring hairpin polyamide (Im-Im-Py(C3H6NHR)-Py-gamma-Im-Py-Py-Py-beta-Dp) with a heptapeptide (R = Ac-Phe-Tyr-Pro-Trp-Met-Lys-Gly-) attached on a central ring was shown to induce cooperative binding of the Drosophila Hox protein cofactor Exd with a Kd of 4.4 nM in vitro, an order of magnitude more efficient than the natural Hox protein partner Ubx. The conjugate joins two sequence specific domains, one for DNA and one for the protein. This small molecule thus serves as a cooperative protein-DNA dimerizer, which mimics the natural Hox family of developmental regulators.

Biomimetic Materials↗
PubMed2001

Cyclohexylether delta-Amino Acids: New Leads for Selectivity Filters in Ion Channels Financial support by the Fonds der Chemischen Industrie (FCI), the Volkswagen Foundation, the Pinguin Foundation, and Schering AG is gratefully acknowledged. H.-D.A. thanks the FCI for a PhD fellowship. We thank Dr. B. Ziemer (Humboldt-Universität zu Berlin) for the X-ray structure analysis and Dr. P. Franke (Freie Universität Berlin) for MALDI-TOF mass spectra.

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Journal Article↗