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Jeffrey L. Haddox, Roswell R. Pfister, Donald D. Muccio, Matteo Villain, Charnell I. Sommers, Manjula Chaddha, G. M. Anantharamaiah, Wayne J. Brouillette, Lawrence J. DeLucas; Bioactivity of Peptide Analogs of the Neutrophil Chemoattractant, N-Acetyl-Proline-Glycine-Proline. Invest. Ophthalmol. Vis. Sci. 1999;40(10):2427-2429.
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purpose. The release of N-acetyl-proline-glycine-proline (PGP), a
chemoattractant resulting from direct alkaline hydrolysis of corneal
proteins, is believed to be the initial trigger for neutrophil invasion
into the alkali-injured cornea. The purpose of this study is twofold:
(1) to compare the activity of N-acetyl-PGP with the
bioactivities of other similar synthetic peptides in an effort to
uncover information about this chemoattractant molecule, and (2) to
test these peptide analogs as potential antagonists of N-acetyl-PGP.
methods. The polarization assay was used to measure the potential chemotactic
response of human neutrophils to peptides. Bioactivity was expressed as
the peptide concentration required to produce 50% neutrophil
polarization (EC50). Antagonist activity was expressed as
the peptide concentration required to produce 50% inhibition
(ID50) of polarization activated by N-acetyl-PGP.
results. Peptide bioactivities (EC50) were ranked as follows: APGPR
(0.34 mM) > N-acetyl-PGP (0.5 mM) > N-(PGP)4-PGLG (3 mM) = t-Boc-PGP (3 mM) > N-acetyl-PG (3.4
mM) > N-methyl-PGP (15 mM) = PGP (15 mM) > peptides without detectable activity (t-Boc-PGP-OMe, N-acetyl-P, PG, PGG, GP, GG and gly-pro-hyp). Peptides
with no detectable bioactivity were tested as potential antagonists of
neutrophil polarization induced by N-acetyl-PGP.
Gly-Pro-Hyp inhibited N-acetyl-PGP activation of
polarization at 20 mM (ID50). No other synthetic peptide
demonstrated a capacity for inhibition.
conclusions. The minimum requirement to elicit bioactivity was the presence of
PGP alone or derivatives of PG in which the N-terminal
proline is blocked. Using this approach, active and inactive mimetic
peptides of N-acetyl-PGP were produced. The most active
peptide, APGPR, was equal to or slightly greater than N-acetyl-PGP, suggesting that more potent analogs might
be designed. Gly-pro-hyp was the only inactive peptide analog to
inhibit the chemoattractant.
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