Activation by Peptidases and Cytotoxicity of 2-(L-α-Aminoacyl) Prodrugs of Methotrexate

Serine-, cysteine-, and metalloproteases are widely spread in many pathogenic bacteria, where they play critical functions related to colonization and evasion of host immune defenses, acquisition of nutrients for growth and proliferation, facilitation of dissemination, or tissue damage during infection. Since all the antibiotics used clinically at the moment share a common mechanism of action, acting as inhibitors of the bacterial cell wall biosynthesis or affecting protein synthesis on ribosomes, resistance to these pharmacological agents represents a serious medical problem, which might be resolved by using new generation of antibiotics, possessing a different mechanism of action. Bacterial protease inhibitors constitute an interesting such possibility, due to the fact that many specific as well as ubiquitous proteases have recently been characterized in some detail in both gram-positive as well as gram-negative pathogens. Few potent, specific inhibitors for such bacterial proteases have been reported at this moment except for some signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin, and tetanus neurotoxin inhibitors. No inhibitors of the critically important and ubiquitous AAA proteases, degP or sortase have been reported, although such compounds would presumably constitute a new class of highly effective antibiotics. This review presents the state of the art in the design of such enzyme inhibitors with potential therapeutic applications, as well as recent advances in the use of some of these proteases in therapy.

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“…91 For targeting the tumor site, a pyrase chemically linked to a monoclonal antibody may be useful. 92 …”

Section: A Proteases Of the C10 C11 And C15 Familiesmentioning

confidence: 97%

Bacterial protease inhibitors

Supuran

Scozzafava

Clare

2002

Medicinal Research Reviews

149

120

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Pyrrolidone carboxyl peptidase (Pcp): An enzyme that removes pyroglutamic acid (pGlu) from pGlu‐peptides and pGlu‐proteins

Awade¹,

Cleuziat²,

Gonzalès³

et al. 1994

Proteins

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Pyrrolidone carboxyl peptidase (EC 3.4.11.8) is an exopeptidase commonly called PYRase, which hydrolytically removes the pGlu-proteins. pGlu also known as pyrrolidone carboxylic acid may occur naturally by an enzymatic procedure or may occur as an artifact in proteins or peptides. The enzymatic synthesis of pGlu suggests that this residue may have important biological and physiological functions. Several studies are consistent with this supposition. PYRase has been found in a variety of bacteria, and in plant, animal, and human tissues. For over two decades, biochemical and enzymatic properties of PYRase have been investigated. At least two classes of PYRase have been characterized. The first one includes the bacterial and animal type I PYRases and the second one the animal type II and serum PYRases. Enzymes from these two classes present differences in their molecular weight and in their enzymatic properties. Recently, the genes of PYRases from four bacteria have been cloned and characterized, allowing the study of the primary structure of these enzymes, and their over-expression in heterelogous organisms. Comparison of the primary structure of these enzymes revealed striking homologies. Type I PYRases and bacterial PYRases are generally soluble enzymes, whereas type II PYRases are membrane-bound enzymes. PYRase II appears to play as important a physiological role as other neuropeptide degrading enzymes. However, the role of type I and bacterial PYRases remains unclear. The primary application of PYRase has been its utilization for some protein or peptide sequencing. Development of chromogenic substrates for this enzyme has allowed its use in bacterial diagnosis.

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Mammalian Pyroglutamyl-Peptidase I

Dando¹

2013

Handbook of Proteolytic Enzymes

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Activation by Peptidases and Cytotoxicity of 2-(L-α-Aminoacyl) Prodrugs of Methotrexate

Cited by 3 publications

References 5 publications

Bacterial protease inhibitors

Bacterial protease inhibitors

Pyrrolidone carboxyl peptidase (Pcp): An enzyme that removes pyroglutamic acid (pGlu) from pGlu‐peptides and pGlu‐proteins

Mammalian Pyroglutamyl-Peptidase I

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