Reagents which regulate human pyroglutamyl peptidase-like enzyme and reagents which bind to human pyroglutamyl peptidase-like enzyme gene products can play a role in preventing, ameliorating, or correcting dysfunctions or diseases, including, but not limited to, brain and spinal cord trauma, stroke, and neurodegenerative disorders, such as amyotropic lateral sclerosis and spinocerebellar degeneration.

Bayer Aktiengesellschaft

Regulation of human pyroglutamyl peptidase-like enzyme

The present invention relates to specific inhibitors of the cysteine protease dipeptidyl peptidase I (DP I)which can be used in the treatment of malignant cell degeneration, immune diseases impaired wound healing and metabolic diseases of humans and are represented by the general formula ##STR00001## and the pharmaceutical salts thereof, in which R is a peptide or a branched or unbranched C.sub.1 C.sub.9 alkyl chain, a branched or unbranched C.sub.2 C.sub.9 alkenyl chain, a branched or unbranched C.sub.2 C.sub.9 alkynyl chain, a C.sub.3 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 carbocyclic, C.sub.5 C.sub.14 aryl, C.sub.3 C.sub.9 heteroaryl, C.sub.3 C.sub.9 heterocyclic, all of the above residues optionally being substituted, the residue AS--AS is a dipeptide or a mimetic thereof, AS is an amino acid or a peptide mimetic thereof. The amino acid is peptide bound with R and R' is a branched or unbranched C.sub.1 C.sub.9 alkyl chain, a branched or unbranched C.sub.2 C.sub.9 alkenyl chain, a branched or unbranched C.sub.2 C.sub.9 alkynyl chain, a C.sub.3 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 cycloalkenyl, C.sub.2 C.sub.9 heterocycloalkyl, C.sub.3 C.sub.9 heterocycloalkenyl, C.sub.5 C.sub.14 aryl, C.sub.3 C.sub.9 heteroaryl, C.sub.3 C.sub.9 heterocyclic, whereas the heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocyclic residue can have up to 6 hetero ring atoms, an amino acid or a peptide mimetic thereof, all of the above residues may be optionally substituted, or is H.

Probiodrug AG

Inhibitors of dipeptidyl peptidase I

In this paper, we describe RT-PCR strategies that allowed us to identify and clone members of the NEP-like family. Degenerate oligoncleotide primers corresponding to consensus sequences located on either side of the HEXXH consensus sequence for zincins were designed and used in RT-PCR with mouse and human testis cDNAs. DNA fragments with lengths expected from the sequence of this class of enzympes were obtained. These DNA fragments were cloned and sequenced. Using this PCR strategy and the PCR fragments as probes to screen cDNA libraries, three zincin-like peptidases were identified in addition of known members of the family. The cDNA sequences allowed to derive specific probes for Northern and in situ hybridization, and probe human chromosomes to localize the gene and establish potential links to genetic diseases. Furthermore, these cDNA sequences were used to produce recombinant fusion proteins in Escherichia coli in order to raise specific antibodies. Finally, the cDNA sequences were cloned in mammalian expression vectors and transfected in various mammalian cell lines to produce active recombinant enzymes suitable for testing specific inhibitors.

peptidase/atrophy

Regulation of human pyroglutamyl peptidase-like enzyme

Inhibitors of dipeptidyl peptidase I

Metalloproteases of the neprilysin family

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