Search PubMed⌕ Search

Biomedical subjects

S Natarajan

Publications and source records attributed to S Natarajan.

At least 91 records · Page 5Linked to original sources
PubMed1993

Structure-activity studies of endothelin leading to novel peptide ETA antagonists.

With the goal of producing receptor antagonists, numerous monocyclic and bicyclic endothelin analogs were prepared and tested for vasoconstrictor activity, receptor affinity and functional antagonist activity. Bis-penicillamine endothelin analogs containing Ala or Asn at position 18 were functional antagonists, with Ki values of 20-40 nM but KB values of about 1 microM (e.g., [Pen1,11, Nle7, Ala18]-endothelin-1, Ki = 42 nM, KB = 1.2 microM). While these peptides are antagonists at the ETA receptor, they appear to be at least partial agonists at another receptor subtype.

Amino Acid Sequence↗
PubMed1992

Site-specific biotinylation. A novel approach and its application to endothelin-1 analogs and PTH-analog.

We have developed an expeditious method for the incorporation of the biotinylaminocaproyl moiety on the epsilon-amino group of a lysine residue within a peptide chain in a site-specific manner. Using t-Boc chemistry for the solid phase synthesis approach and a base labile, acid stable protecting group (Fmoc-) for the epsilon-amino group of the target lysine, we prepared fully protected resin bound peptides which are site-specifically biotinylated. Following HF cleavage, the uniquely biotinylated peptides were obtained in a high degree of purity. Using this approach, a number of biotinylaminocaproyllysyl derivatives of a monocyclic Endothelin-1 analog were prepared. Synthesis of selected bicyclic analogs of high affinity monocycles led to the preparation of the bicyclic [Nle7]ET-1 analog containing epsilon-biotinylaminocaproyllysine at position-9. This peptide, with Kd = 0.08 nM, has 1000-fold higher affinity for the ETA receptor than the commercially available N alpha-biotinylated Endothelin-1. The general utility of this biotinylation methodology was demonstrated by the synthesis of a site-specifically biotinylated PTH analog which contained several side chain functionalized amino acid residues in its sequence. The synthetic method reported here is convergent in that it allows the facile variation of the length of the spacer and also offers the potential to introduce in a site specific manner other groups such as affinity labels and fluorescent tags.

Amino Acid Sequence↗
PubMed1991

Replication terminator protein of Escherichia coli is a transcriptional repressor of its own synthesis.

We have investigated the regulation of synthesis of the replication terminator protein (Ter) of Escherichia coli and have discovered that the protein is a repressor of its own synthesis at the transcriptional step. Since the synthesis of Ter protein was observed to be down-regulated in vivo, these results are consistent with autoregulation as one control mechanism of Ter protein within the cell. Analysis of the tus gene that encodes the Ter protein revealed that transcription was initiated from a single promoter located within the upstream nontranscribed sequence. In vitro footprinting experiments have revealed that Ter protein prevented binding of RNA polymerase to the promoter sequence when both proteins were incubated with promoter DNA. However, once bound to the promoter, RNA polymerase could not be displaced by Ter protein. Conversely, prebound Ter protein could not be dislodged from its binding site at the promoter when challenged with RNA polymerase. Therefore, Ter protein can serve as a transcriptional repressor of its own synthesis by preventing RNA polymerase from binding to the tus promoter when both proteins are present in the cell milieu.

Bacterial Proteins↗
PubMed1991

Crystal and molecular structure of L-valyl-L-lysine hydrochloride.

L-Valyl-L-lysine hydrochloride, C11N3O3H23 HCl, crystallizes in the monoclinic space group P2(1) with a = 5.438(5), b = 14.188(5), c = 9.521(5) A, beta = 95.38(2) degrees and Z = 2. The crystal structure, solved by direct methods, refined to R = 0.036, using full matrix least-squares method. The peptide exists in a zwitterionic form, with the N atom of the lysine side-chain protonated. The two gamma-carbons of the valine side-chain have positional disorder, giving rise to two conformations, chi 1(11) = -67.3 and 65.9 degrees, one of which (65.9 degrees) is sterically less favourable and has been found to be less popular amongst residues branching at beta-C. The lysine side-chain has the geometry of g- tgt, not seen in crystal structures of the dipeptides reported so far. Interestingly, chi 2(3) (63.6 degrees) of lysine side-chain has a gauche+ conformation unlike in most of the other structures, where it is trans. The neighbouring peptide molecules are hydrogen bonded in a head-to-tail fashion, a rather uncommon interaction in lysine peptide structures. The structure shows considerable similarity with that of L-Lys-L-Val HCl in conformational angles and H-bond interactions [4].

Dipeptides↗
PubMed1990

Isolation and characterization of a repetitive DNA element from the genome of the human filarial parasite, Brugia malayi.

The genome of the human filarial parasite Brugia malayi contains at least two major repetitive DNA elements. One, referred to as the HhaI family, consists of 10(4)-10(5) tandemly arrayed copies per haploid genome of a monomer of 322 base pairs and does not contain a cleavage site for the restriction endonuclease MboI. We constructed a library of MboI-digested genomic B. malayi DNA in BamHI-cut M13mp18 resulting in the exclusion of the HhaI repeat family from the library. Hybridization of this genomic library with nick-translated genomic DNA yielded several copies of a repeat family which we have named the BmMboI family. From sequence analysis of more than 50 monomers, which differ from each other in sequence and length, we have been able to divide the monomers into several regions based on the level of sequence conservation. Southern blot analyses of B. malayi genomic DNA digested with a variety of restriction endonucleases and probed with the isolated repeat demonstrate multiple bands of varying sizes except with HindIII-cut DNA, where the repeat is found only in very high-molecular-weight DNA.

Animals↗
PubMed1989

Crystal and molecular structure of sarcosine.

The crystal structure of sarcosine in pure form has been determined at low temperature (135 K). The crystals are othorhombic, space group P2(1)2(1)2(1) with unit cell dimensions a = 6.687(2) A, b = 7.899(3) A, c = 8.607(3) A. On the basis of 988 reflections with intensities larger than 3 sigma (I) the structure was refined to a conventional R-factor of 0.034 to give e.s.d. in bond lengths of 0.002 A and 0.2 degrees in angles. The molecule is extended and exists in the zwitterionic form. There is a small deviation from planarity in the alpha-amino acid group as well as in the main chain.

Crystallization↗
PubMed1988

Ketomethylureas. A new class of angiotensin converting enzyme inhibitors.

The design rationale for a new series of tripeptide derived angiotensin converting enzyme (ACE) inhibitors, which we term "ketomethylureas", is described. Analogs of tripeptide substrates (i.e. N-benzoyl-Phe-Ala-Pro) in which the nitrogen atom of the scissile amide bond and the adjacent asymmetric carbon atom of the penultimate amino acid residue are formally transposed give rise to this novel class of inhibitors. The most potent ketomethylureas inhibit ACE with I50 values in the nM range.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Rational design and biochemical utility of specific inhibitors of angiotensin-converting enzyme.

Angiotensin-converting enzyme (ACE), the receptor for an important new class of antihypertensive drugs, is now one of the better studied zinc metallopeptidases. The development of several classes of tightly binding competitive inhibitors of ACE has led to increased understanding of the structure and function of this enzyme while also yielding important new drugs for the diagnosis and treatment of hypertensive disease. Peptides from snake venom provided the first proof of the therapeutic utility of ACE inhibitors, and a tripeptide sequence, Phe-Ala-Pro, was used as a model for sidechain interactions with ACE in the rational design of simpler nonpeptidic inhibitors such as captopril and enalapril. These and more recently developed ACE inhibitors can be classified according to their structural analogy to dipeptides or tripeptides and according to the nature of their zinc-binding ligands, such as sulfhydryl, ketone, carboxylate, or hydroxyphosphinyl, that contribute greatly to their binding to ACE. Several newer ACE inhibitors have increased potency and/or improved pharmacokinetic properties due to modifications such as substitution of the proline ring or replacement of the methyl side chain analogous to Ala by an aminobutyl residue analogous to Lys. The availability of structurally diverse ACE inhibitors with great potency and specificity provides a powerful biochemical tool for purification, localization, and characterization of ACE in different tissues, and for distinguishing related zinc metallopeptidases with similar properties.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Management of giant retinal breaks.

A retrospective study involving 40 eyes of 40 patients with giant retinal break is presented. A comparison is attempted between cases where silicone oil is used and in cases where it was not used. The final success rate was found to be same in the two groups on long term follow-up.

Adolescent↗