title: Aspartic proteases in drug discovery.
abstract: Aspartic proteases are the smallest class of human proteases with only 15 members. Over the past years, they have received considerable attention as potential targets for pharmaceutical intervention since many have been shown to play important roles in physiological and pathological processes. Despite numerous efforts, however, the only inhibitors for aspartic proteases currently on the market are directed against the HIV protease, an aspartic protease of viral origin. Nevertheless, several inhibitors including those targeting renin, BACE1 and gamma-secretase are in clinical or preclinical development, and some other aspartic proteases are discussed as potential drug target. The crystal structures of seven human aspartic proteases have now been solved and, together with a detailed kinetic understanding of their catalytic mechanism, this has greatly contributed to the design and discovery of novel inhibitors for this protease class. This review describes current aspartic protease drug targets and summarizes the drug discovery efforts in this field. In addition, it highlights recent developments which may lead to a new generation of aspartic protease inhibitors.
authors.affiliation: Novartis Institutes for BioMedical Research, Expertise Platform Proteases, CH-4002 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Eder
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hommel
authors.forename: Frederic
authors.initials: F
authors.lastname: Cumin
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerhartz
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017076:Computer-Aided Design; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D053763:Presenilins / Q000037:antagonists & inhibitors / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D012083:Renin / Q000737:chemistry; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; D017320:HIV Protease Inhibitors; D008565:Membrane Proteins; D053763:Presenilins; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors; C460085:signal peptide peptidase