Arginase Inhibitors: A Rational Approach Over One Century.

Arginase (EC 3.5.3.1) is the bimanganese enzyme that converts L-arginine into ornithine and urea. This enzyme was discovered more than a century ago and early α-amino acids were identified as weak inhibitors. It was only during the 90s, after nitric oxide (NO) was reported as one of the most important biological mediators and when tight interrelation of arginase and NO synthase was found, that the development of arginase inhibitors was accelerated. The regulation of arginase activity by the N-hydroxy-L-arginine (3, NOHA) intermediate of the NO synthesis was the starting point of the N-hydroxy-nor-arginine (21, nor-NOHA) that proved to be the first micromolar inhibitor. The previously known manganese and arginase binding by borate inspired the 2(S)-amino-6-boronohexanoic acid (39, ABH) and S-(2-boronoethyl)-L-cysteine (40, BEC) now both considered as reference compounds in arginase inhibition. The high-resolution crystal structure of arginase and molecular modeling has rendered possible the recent design of (53) the strongest α,α-disubstituted derivatives of ABH. Simultaneously, traditional medicinal plants have contributed as a source of molecular diversity to the discovery of arginase inhibitors. This rational, step-by-step approach serves as guide in the present review where emphasis is placed on structure activity relationships. Highlights exhaustive review on arginase inhibitors highlight is made on rational approach to conception and structure activity relationships evaluation model is systematically mentioned with results.

Protease inhibitors and their peptidomimetic derivatives as potential drugs.

Precise spatial and temporal regulation of proteolytic activity is essential to human physiology. Modulation of protease activity with synthetic peptidomimetic inhibitors has proven to be clinically useful for treating human immunodeficiency virus (HIV) and hypertension and shows potential for medicinal application in cancer, obesity, cardiovascular, inflammatory, neurodegenerative diseases, and various infectious and parasitic diseases. Exploration of natural inhibitors and synthesis of peptidomimetic molecules has provided many promising compounds performing successfully in animal studies. Several protease inhibitors are undergoing further evaluation in human clinical trials. New research strategies are now focusing on the need for improved comprehension of protease-regulated cascades, along with precise selection of targets and improved inhibitor specificity. It remains to be seen which second generation agents will evolve into approved drugs or complementary therapies.

Clinical role of beta-lactam/beta-lactamase inhibitor combinations.

The use of beta-lactamase inhibitors in combination with beta-lactam antibiotics is currently the most successful strategy to combat a specific resistance mechanism. Their broad spectrum of activity originates from the ability of respective inhibitors to inactivate a wide range of beta-lactamases produced by Gram-positive, Gram-negative, anaerobic and even acid-fast pathogens. Clinical experience confirms their effectiveness in the empirical treatment of respiratory, intra-abdominal, and skin and soft tissue infections. There is evidence to suggest that they are efficacious in treating patients with neutropenic fever and nosocomial infections, especially in combination with other agents. beta-Lactam/beta-lactamase inhibitor combinations are particularly useful against mixed infections. Their role in treating various multi-resistant pathogens such as Acinetobacter species and Stenotrophomonas maltophilia are gaining importance. Although, generally, they do not constitute reliable therapy against extended-spectrum beta-lactamase producers, their substitution in place of cephalosporins appears to reduce emergence of the latter pathogens. Similarly, their use may also curtail the emergence of other resistant pathogens such as Clostridium difficile and vancomycin-resistant enterococci. beta-Lactam/beta-lactamase inhibitor combinations are generally well tolerated and their oral forms provide effective outpatient therapy against many commonly encountered infections. In certain scenarios, they could even be more cost-effective than conventional combination therapies. With the accumulation of so much clinical experience, their role in the management of infections is now becoming more clearly defined.