Irreversible inhibition of serine proteases by peptide derivatives of (. alpha. -aminoalkyl)phosphonate dephenyl esters

Journal Article · Tue Jan 01 00:00:00 EST 1991 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00216a026· OSTI ID:5670774

Oleksyszyn, J; Powers, J C ^[1]

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1. Georgia Inst. of Tech., Atlanta (USA)

Peptidyl derivatives of diphenyl ({alpha}-aminoalkyl)phosphonates have been synthesized and are effective and specific inhibitors of serine proteases at low concentration. Z-Phe{sup P}(OPh){sub 2} irreversibly reacts with chymotrypsin and does not react with two elastases. The best inhibitor for most chymotryspin-like enzymes including bovine chymotrypsin, cathespin G, and rat mast cell protease II is the tripeptide Suc-Val-Pro-Phe{sup P}(OPh){sub 2} which corresponds to the sequence of an excellent p-nitroanilide substrate for several chymases. The valine derivative Z-Val{sup P}(OPh){sub 2} is specific for elastase and reacts with human leukocyte elastase but not with chymotrypsin. The tripeptide Boc-Val-Pro-Val{sup P}(OPh){sub 2}, which has a sequence found in a good trifluoromethyl ketone inhibitor of HLE, is the best inhibitor for HLE and porcine pancreatic elastase. The rates of inactivation of chymotrypsin by MeO-Suc-Ala-Ala-Pro-Phe{sup P}(OPh){sub 2} and PPE and HLE by MeO-Suc-Ala-Ala-Prov-Val{sup P}(OPh){sub 2} were decreased 2-5 fold in the presence of the corresponding substrate, which demonstrates active site involvement. Only one of two diastereomers of Suc-Val-Pro-Peh{sup P}(OPh){sub 2} reacts with chymotrypsin and the enzyme-inhibitor complex had one broad signal at 25.98 ppm in the {sup 31}P NMR spectrum corresponding to the Ser-195 phosphonate ester. Phosphonylated serine proteases are extremely stable since the half-time for reactivation was {ge}48 h for the inhibited elastases and 7.5-26 h for chymotrypsin. Peptidyl derivatives of diphenyl ({alpha}-aminoalkyl)phosphonates are relatively easy to synthesize, are chemically stable in buffer and in human plasma, form very stable derivatives with serine proteases, do not react with acetylcholinesterase, and thus should have considerable potential utility as therapeutic agents.

• OSTI ID: 5670774
• Journal Information: Biochemistry; (United States), Vol. 30:2; ISSN 0006-2960
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
PHOSPHONIC ACID ESTERS
DERIVATIZATION
SERINE PROTEINASES
NUCLEAR MAGNETIC RESONANCE
ENZYME INHIBITORS
INHIBITION
PHOSPHORUS 31
VALINE
AMINO ACIDS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
ENZYMES
ESTERS
HYDROLASES
ISOTOPES
LIGHT NUCLEI
MAGNETIC RESONANCE
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC PHOSPHORUS COMPOUNDS
PEPTIDE HYDROLASES
PHOSPHORUS ISOTOPES
RESONANCE
STABLE ISOTOPES
550601* - Medicine- Unsealed Radionuclides in Diagnostics