Krishnan P. Nambiar

The ribonuclease from an extinct bovid ruminant

The sequence of the ribonuclease from the ancestor of swamp buffalo, river buffalo, and ox, corresponding approximately to Pachyportax latidens, an extinct ruminant known from the fossil record, has been reconstructed using the rule of ‘maximum parsimony’. This protein and two sequences that may have been intermediates in the evolution of modern ribonuclease have been constructed in the laboratory by site‐directed mutagenesis, and their properties examined.

Redesigning nucleic acids

A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.

A Stereoselective Synthesis of α - and β-2′-Deoxy-2-thiouridine

Abstract A stereoselective glycosylation procedure is described for the synthesis of protected α- and β-2′-deoxy-2-thiouridine (dS2U) in 68% and 94% yield, respectively. Evidence is presented that suggests the reaction proceeds through a silylated thio-glycoside intermediate. This intermediate undergoes an efficient S2 → N1 rearrangement mediated by SnCl4. The phosphoramidite and phosphodiester synthons and a dS2U dinucleotide are also synthesized and the X-ray structure of β-dS2U is presented.

Efficient desulfurization of 2-thiopyrimidine nucleosides to the corresponding 4-pyrimidinones

Abstract A procedure is described for the preparation of 2′-deoxy-4-pyrimidone (dH 2 U) and 2′-deoxy-5-methyl-4-pyrimidone (dH 2 T) nucleosides. The key transformation is a newly quantitative desulfurization of the corresponding 2-thio analogue by a brief treatment with a m -chloroperbenzoic acid/pyridine solution. The phosphoramidites of these nucleosides have also been synthesized.

Efficient synthesis of α-purine nucleosides of 2-deoxyribofuranose and 2-deoxyribopyranose

A high yield synthesis of α-purine nucleosides of 2-deoxyribofuranose and 2-deoxyribopyranose is reported starting from 1,3,5-tri-O-acetyl-2-deoxyribofuranose and 1,3,5,-tri-O-acetyl-2-deoxyribopyranose with silylated purines under Lewis acid (SnCl4) catalysed conditions.

Strain-free disulfide bridge and stabilization of β-ribbon structures in short peptides

Designing water soluble peptides which adopt -ribbon structures in aqueous solution is a challenging problem in modern bioorganic chemistry [1,2]. We had shown earlier that a disulfide cross link formed between the side-chains of -amino-mercaptohexanoic acid residues in peptides is a lot more effective in enhancing the stability of -ribbon structure of the peptide as compared to the disulfide bridge formed between cysteine residues [3]. We observed similar stabilization when the disulfide bridge is made up of six atoms [4]. In order to evaluate the effect of the disulfide bridge length on -ribbon conformation, we synthesized short peptides containing cysteine, homocysteine, (S)-amino-mercaptopentanoic acid (Amp) and (S)-amino-mercaptohexanoic acid (Amh) and converted them into disulfide bridged dimers. Peptides with longer disulfide bridge show more pronounced -ribbon character in comparison to the cystine peptide.

Design, Synthesis and Incorporation in Peptides of a β-Turn Mimetic

Designing peptides and proteins that fold into predetermined secondary structures is a challenging biochemical problem. α-Helix, β-ribbon and turns are landmark protein secondary structures. While major advances have been made in the design of α-heli-ces, designing water-soluble β-ribbon structures and turns are under active investigation. Several unnatural turn structures have been designed for incorporation into peptides to enhance their folding to yield β-ribbon structures [1–5]. Most of these models involve complex ring systems, which require multistep synthesis. Using model building and computer graphics, we designed a simple β-turn mimic (Figure 1) using three simple building blocks, β-alanine, 3-amino-5-nitrobenzoic acid and sarcosine. Our model forms a nice hydrophobic interior while assuming a β-turn structure. We reasoned this to be quite favorable in aqueous solution.