Anthony W. Czarnik

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Neomycin inhibits the binding of Tat-derived peptides to the trans-activating region (TAR) of HIV-1 RNA. Kinetic studies reveal that neomycin acts as a noncompetitive inhibitor that can bind to the Tat-TAR complex and increase the rate constant (koff) for dissociation of the peptide from the RNA. Neomycin effects a conformational change in the structure of(More)
TAR RNA represents an attractive target for the intervention of human immunodeficiency virus type 1 (HIV-1) replication by small molecules. We now describe three small molecule inhibitors of the HIV-1 Tat-TAR interaction that target the RNA, not the protein. The chemical structures and RNA binding characteristics of these inhibitors are unique for each(More)
Assuming that the chemical reactions used to synthesize a combinatorial library member are successful, then knowledge of the specific reaction sequence is equivalent to knowing the member's chemical identity. Because the determination of chemical identity is typically not automatable and requires a substantial amount of material, schemes that encode a(More)
To Pasteur’s famous dictum, ‘‘Chance favors the prepared mind,’’ could arguably be added the corollary, ‘‘As the number of chances increases, so increases the effect of favor.’’ It is nearly a truism that a great many important discoveries in chemistry originated not from careful design, but from astute observations of unintended experiments. Suppose, then,(More)
We have developed a therapeutic program focusing on the inhibition of a human immunodeficiency virus-1 specific protein-RNA interaction. This program begins with a search for small organic molecules that would interfere with the binding of Tat protein to TAR RNA. The methodologies chosen to study the HIV-1 Tat-TAR interaction and inhibition include gel(More)
A major objective of the DIVERSOMER® technology is to provide pure and characterized compounds for biological testing in order to prevent ‘false negatives’ in our libraries. On several occasions, analysis of the final products by1H-NMR and MS, has revealed by-products from the polystyrene solid support. Subsequently, three alternative methods were studied(More)
Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some(More)
The list of biologically active small molecules for which fluorescent sensors would be desirable is enormous. The list of sensors actually available is surprisingly small. The reason derives in part from a lack of communication between chemistry inventors and biology end-users. A new World Wide Web board has been created to address this need.
Self-splicing group I intron RNA was chosen as a potential therapeutic target for small-molecule intervention. High-throughput screening methodologies have been developed to identify small organic molecules that regulate the activities of these catalytic introns. Group introns derived from pathogenic Pneumocystis carinii and phage T4 were used as model(More)
To evaluate some synthetic catalysts that mimic ribonuclease, a quantitative assay has been developed that measures the number of phosphate diester bonds cleaved in a polymeric RNA substrate. This assay involves determining the number of 5'-oligonucleotide termini produced during the cleavage, using polyuridylic acid as the substrate. Samples withdrawn from(More)