Biomedical subjects
Publications and source records attributed to S Natarajan.
Bilateral first-rib hypoplasia, a skeletal anomaly not previously associated with the nail-patella syndrome, is reported occurring in a young woman possessing numerous other features of this potentially lethal condition.
The Koebner phenomenon, often a feature of psoriasis, lichen planus, warts, and erythema multiforme, is documented in a patient with anaphylactoid purpura.
A new amino alcohol modification designed to mimic the putative transition-state of amide bond cleavage by proteolytic enzymes has been incorporated into the scissile bond position of N-benzoyl-Phe-Ala-Pro, a known substrate of angiotensin converting enzyme (ACE). The resulting modified tripeptides (i.e. 4) are shown to be a new class of potent inhibitors of converting enzyme.
A case of pagetoid reticulosis is presented. Histopathology showed infiltration of the epidermis by mononuclear cells. Twenty percent of the mononuclear cells showed the presence of lysozyme indicating a histiocytic origin. Electron microscopy confirmed the presence of lymphocytes and histiocytes but these cells were outnumbered by Sézary cells. The presence of large numbers of Sézary cells indicates that pagetoid reticulosis is a cutaneous T-cell lymphoma closely related to mycosis fungoides.
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The design rationale for a new series of angiotensin-converting enzyme (ACE) inhibitors which incorporate a ketone substituent into a peptide backbone is described. Molecular regions which were expected to mimic the binding of an N-acyl tripeptide substrate at secondary binding sites S1 and S1' were systematically varied in order to study the specificity of inhibitor binding and optimize inhibition against ACE. The most effective ketomethyldipeptides inhibit ACE in the 10(-9) M range.
Results of an investigation aimed at identifying the consequences of chemical modifications of the alpha-aminoketone moiety of ketomethyldipeptides on angiotensin converting enzyme (ACE) inhibition are reported. These studies lead to the conclusion that within this series, the optimal structural backbone formulation for inhibition of ACE is represented by 1. Introduction of a Sar-Pro C-terminal dipeptide in this system, in contrast to other inhibitor classes, is compatible with potent inhibitory activity. Other structure-activity relationships for ketomethyldipeptides and related derivatives are presented, and speculations on possible modes of binding of these inhibitors to ACE, and on the question of ketone rehybridization are offered.
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Twenty-five patients of leprosy classified according to the criteria of Ridley and Jopling (1966) were studied to verify the existence of isopathic phenomenon, using lepromin and autoclaved BCG as antigens. BCG as well as lepromin injection sites showed tuberculoid granulomas in all the cases of tuberculoid, borderline tuberculoid, mid-borderline and indeterminate leprosy. In lepromatous and borderline lepromatous cases BCG injection sites showed infiltration of foam cells containing AFB and foci of epithelioid cells, while lepromin injection sites showed infiltration of foam cells containing AFB only. These findings in the present study do not support the occurrence of isopathic phenomenon in leprosy with BCG.
We tested the synthetic C-terminal heptapeptide of cholecystokinin, which has the same biologic activity as cholecystokinin, and various synthetic analogs of the C-terminal heptapeptide for their abilities to increase amylase secretion from dispersed acini prepared from guinea-pig pancreas. We found that altering the chemical character of the amino acid in position 27 altered the potency with which the peptide stimulated amylase secretion but did not alter the efficacy of the peptide. We also found that, in the amino acid in position 27, the major function of the side-chain seems to be to position to the sulfate ester group at a proper distance from the backbone of the peptide chain, whereas the chemical structure of the side-chain per se seems to be of relatively minor importance.
To explore the importance of the charge of the amino acid in position 15 in influencing the apparent affinities of VIP and secretin for their receptors on pancreatic acinar cells, we tested the synthetic C-terminal 23-peptide fragment of secretin (S5-27) and two analogues containing substitutions in position 15 for their abilities to interact with secretin-preferring and VIP-preferring receptors on pancreatic acinar cells. In inhibiting the increase in cyclic AMP caused by VIP acting through the VIP-preferring receptors, 15-Lys-S5-27 was equipotent with 15-Asn-S5-27, and these analogues were significantly more potent than S5-27. In inhibiting the increase in cyclic AMP caused by secretin acting through the secretin-preferring receptors, S5-27 was equipotent with 15-Asn-S5-27, and these peptides were significantly more potent than 15-Lys-S5-27. These findings indicate that the affinities of these 23-peptides for the VIP-preferring receptors and for the secretin-preferring receptors were influenced primarily by the absence of a particular charge in position 15 but not by the presence of the opposite charge.
The C-terminal tricosapeptide of secretin (S5-27) and two analogues, one with asparagine replacing aspartic acid in position 15 (15-Asn-S5--27) and one with lysine replacing aspartic acid in position 15 (15-Lys-S5-27) were tested for their abilities to interact with hormone receptors on pancreatic acinar cells. In interacting with the receptors which prefer vasoactive intestinal peptide (vasoactive intestinal peptide-preferring receptors), the apparent affinity of 15-Asn S5-27 was equal to that of 15-Lys-S5-27 and was greater than that of S5-27. In interacting with secretin-preferring receptors, the apparent affinity of 15-Asn-S5--27 was equal to that of S5-27 and was greater than that of 15-Lys-S5-27. In interacting with the secretin-preferring receptors each of the secretin fragments was approximately 2% as effective as secretin in causing an increase in cellular cyclic AMP. None of these fragments was able to cause a detectable increase in cyclic AMP mediated by the vasoactive intestinal peptide-preferring receptors. The dose vs. response curves for the action of secretin and vasoactive intestinal peptide on cellular cyclic AMP and on amylase secretion as well as the pattern of effects of secretin fragments on these actions indicated that the increase in amylase secretion caused by vasoactive intestinal peptide and secretin is mediated exclusively by the vasoactive intestinal peptide-preferring receptors. Furthermore, occupation of approximately 50% of the vasoactive intestinal peptide-preferring receptors is sufficient to cause maximal stimulation of amylase secretion.
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The 23-peptide 15-lysine-secretin-(5-27) [S(5-27)] was synthesized on an insoluble support. The residue in position 15 of secretin, aspartic acid, was replaced by lysine, which occupies that position in the vasoactive intestinal polypeptide (VIP), a member of the secretin family. The resulting analogue showed increased VIP-like activity on smooth muscle preparations and unaltered secretin-like activity on pancreatic juice secretion in the rat. The affinity of the new analogue was high-affinity secretin receptors in acinar cells from guinea pig pancreas was less than that of S(5-27) but was higher than that of S(5-27) for high-affinity VIP receptors in the same cells.
The solution conformation of a 7-peptide with the C-terminal sequence of cholecystokinin was investigated by evaluation of intramolecular resonance energy transfer between tyrosine (donor) in position 1 and tryptophan (acceptor) in position 4. From the relative enhancement of acceptor fluorescence a transfer efficiency of 0.70 +/- 0.04 was determined. The use of this parameter in Förster's equation permitted the calculation of the average intramolecular tyrosine-tryptophan separation, whereby the assumption of random donor-acceptor orientation was made. The resulting average distance of 10.0 +/- 0.3 A suggests some type of a folded conformation and excludes the existence of a fully extended chain in the N-terminal part of the peptide. A comparison with tyrosine-tryptophan distances observed in other biologically active polypeptides is made.
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The influence of tyrosine O-sulfate, the 27th residue in the sequence of cholecystokinin (pancreozymin) (CCK-PZ) on calcium outflux in isolated pancreatic cells of guinea pigs, was studied by replacing this residue in the biologically active C-terminal heptapeptide, CCK-PZ-(27--33) (I), with L-serine O-sulfate. The synthetic analogue Ser(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2 (IV), produced the half-maximal outflux observed with I, if applied at about 250 times higher concentration. The unsulfated form of IV was about ten times less potent than unsulfated I. Thus, in the effect on the calcium outflux, serince cannot replace tyrosine without a major loss in potency; a sulfate ester group in position 27 is important but in itself not sufficient for full potency. Interestingly, if the terminal amino group of the heptapeptide is left protected by a tert-butyloxycarbonyl group, the potencies of the derivatives of both I and IV were slightly, but significantly, higher than those of the free peptides.