PMID- 2353815
OWN - NLM
STAT- MEDLINE
DCOM- 19900718
LR  - 20190628
IS  - 0003-9861 (Print)
IS  - 0003-9861 (Linking)
VI  - 280
IP  - 1
DP  - 1990 Jul
TI  - Structure-activity studies of fluoroketone inhibitors of alpha-lytic protease and 
      human leukocyte elastase.
PG  - 137-46
AB  - We have synthesized a series of peptidyl fluoroketones that reversibly inhibit 
      the serine proteases human leukocyte elastase (HLE) and alpha-lytic protease 
      (alpha-LP). Ac-ambo-AlaCF3 (1) inhibits HLE and alpha-LP with Ki's of 2.4 and 15 
      mM, respectively. The effects of structural variations on this parent compound on 
      Ki and the kinetics of inhibition were studied. The acetyl group was replaced by 
      the tripeptide Z-L-Ala-L-Ala-L-Pro to yield the tetrapeptide trifluoroketone 
      (TFK) Z-L-Ala-L-Ala-L-Pro-ambo-AlaCF3 (2). This extension reduced Ki 3500-fold 
      for HLE and 3000-fold for alpha-LP. Removal of a fluorine atom from a TFK 
      decreases Ki about 15- to 30-fold with both enzymes. Replacement of one fluorine 
      atom of 2 by a residue (-CH2-CH2-COLeuOMe) (6) which can interact with the S'1 
      and S'2 subsites decreased Ki 30-fold for HLE and 150-fold for alpha-LP compared 
      to Z-L-Ala-L-Ala-L-Pro-ambo-AlaCF2H (3). The Ki of 6 for HLE is approximately 
      equal to that of trifluoroketone 2. For alpha-LP Ki of 6 is 10-fold lower than 
      that for the trifluoroketone 2. Inhibitors with Ki values less than 10(-7) M 
      exhibit slow binding kinetics. By analogy to cholinesterases and chymotrypsin, it 
      is likely that these enzymes combine with the keto form of the inhibitor to form 
      the enzyme-inhibitor complex. Therefore, kon and Ki were corrected for the ketone 
      concentration. The corrected kon values for the slow binding inhibitors are in 
      most cases less than diffusion controlled, ranging between 8.2 X 10(4) and 4.68 X 
      10(6) M-1 s-1. An exception is Z-L-Ala-L-Ala-L-Pro-ambo-ValCF3 (8) where kon = 9 
      X 10(7) M-1 s-1, which is nearly diffusion controlled.
FAU - Govardhan, C P
AU  - Govardhan CP
AD  - Brandeis University, Graduate Department of Biochemistry, Waltham, Massachusetts 
      02254.
FAU - Abeles, R H
AU  - Abeles RH
LA  - eng
GR  - GM12633-26/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Arch Biochem Biophys
JT  - Archives of biochemistry and biophysics
JID - 0372430
RN  - 0 (Ketones)
RN  - 0 (Oligopeptides)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Serine Proteinase Inhibitors)
RN  - 284SYP0193 (Fluorine)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.21.12 (myxobacter alpha-lytic proteinase)
RN  - EC 3.4.21.36 (Pancreatic Elastase)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Fluorine
MH  - Humans
MH  - Ketones/chemical synthesis/*pharmacology
MH  - Kinetics
MH  - Leukocyte Elastase
MH  - Magnetic Resonance Spectroscopy
MH  - Molecular Sequence Data
MH  - Oligopeptides/chemical synthesis/*pharmacology
MH  - Pancreatic Elastase/*antagonists & inhibitors
MH  - Protease Inhibitors/*pharmacology
MH  - *Serine Endopeptidases
MH  - *Serine Proteinase Inhibitors
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
EDAT- 1990/07/01 00:00
MHDA- 1990/07/01 00:01
CRDT- 1990/07/01 00:00
PHST- 1990/07/01 00:00 [pubmed]
PHST- 1990/07/01 00:01 [medline]
PHST- 1990/07/01 00:00 [entrez]
AID - 0003-9861(90)90528-7 [pii]
AID - 10.1016/0003-9861(90)90528-7 [doi]
PST - ppublish
SO  - Arch Biochem Biophys. 1990 Jul;280(1):137-46. doi: 10.1016/0003-9861(90)90528-7.