A new class of angiotensin-converting enzyme inhibitors

Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.     

Chronic active hepatitis in mice induced by 3-hydroxy-4-pyrone

Summary Chronic active hepatitis was selectively induced in mice by the feeding of a diet containing 3-hydroxy-4-pyrone (0.5% by weight) for periods of 6 weeks and longer. This model should be of particular value in elucidating the pathogenesis of drug-induced forms of chronic active hepatitis. Maltol (3-hydroxy-2-methyl-4-pyrone) did not produce any liver lesion.Acknowledgment. This research was supported in part by a grant from the Sir A.E. Rowden White Bequest to the Department of Pathology, University of Melbourne.To whom correspondance and requests for reprints should be addressed.     

A possible method for improving the efficacy of dapsone

Summary The antileprosy drug dapsone is unable to penetrate intactMycobacterium leprae in vitro, as determined by its effect on o-diphenoloxidase in the bacilli. When combined with the peptide polylysine, the sulfone drug passes through the bacterial cell membranes, and penetrates the enzyme protein, resulting in a 100% inhibition of its activity.     

Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease

The DSCR1 (Adapt78) gene¹ is transiently induced by stresses to temporarily protect cells against further potentially lethal challenges. However, chronic expression of the DSCR1 (Adapt78) gene has now been implicated in several pathological conditions including Alzheimer’s disease, Down syndrome and cardiac hypertrophy. Calcipressin 1 has been shown to function through direct binding and inhibition of the serine threonine protein phosphatase Calcineurin. Pharmacological inhibition of calcineurin, by the immunosuppressive drugs cyclosporin A and FK506, affects a wide variety of diseases. It is, therefore, likely that this endogenous calcineurin inhibitor, calcipressin 1, may also play a role in a variety of human diseases. ¹Please note that the mammalian DSCR1 gene is also called Adapt78 or RCAN1, and its protein products have been named Calcipressin1, MCIP1 and RCAN1. A proposal to adopt a single gene name of RCAN1 and a protein name RCAN1 (for Regulator of Calcineurin) has been endorsed by the HUGO Gene Nomenclature Committee, but final approval must await agreement from a majority of researchers in the field. Received 2 March 2005; received after revision 27 May 2005; accepted 19 July 2005     

Local positional cues in the neuroepithelium guide retinal axons in embryonic Xenopus brain

Growing retinal axons home to their distant target, the tectum, even when they are displaced from their normal pathway. This argues for long-range guidance mechanisms in the embryonic brain. Growth cones may orientate to diffusible attractants released from the target, as proposed in other systems, or they may use a stable distribution of positional information in the neuroepithelium. To distinguish between these possibilities, small pieces of the presumptive optic tract, through which retinal axons will normally grow, were rotated by approximately 90 degrees either clockwise or counterclockwise. When the retinal axons later encountered the rotated neuroepithelium, they also turned clockwise or counterclockwise, in correspondence with the direction of rotation. This demonstrates that long-range navigation of retinal axons in the vertebrate brain is based partly on stable, local positional factors, rather than on remote diffusible factors.