Methotrexate analogs. 26. Inhibition of dihydrofolate reductase and folylpolyglutamate synthetase activity and in vitro tumor cell growth by methotrexate and aminopterin analogs containing a basic amino acid side chain

1986 ◽  
Vol 29 (5) ◽  
pp. 655-660 ◽  
Author(s):  
Andre Rosowsky ◽  
James H. Freisheim ◽  
Richard G. Moran ◽  
Vishnu C. Solan ◽  
Henry Bader ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Dihydrofolate Reductase ◽  
Basic Amino Acid ◽  
Side Chain ◽  
Synthetase Activity ◽  
Amino Acid Side Chain ◽  
Tumor Cell Growth ◽  
Folylpolyglutamate Synthetase

scholarly journals Mechanism by Which Mutations at His274 Alter Sensitivity of Influenza A Virus N1 Neuraminidase to Oseltamivir Carboxylate and Zanamivir

2002 ◽  
Vol 46 (12) ◽  
pp. 3809-3816 ◽  
Author(s):  
Michael Z. Wang ◽  
Chun Y. Tai ◽  
Dirk B. Mendel
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Influenza A ◽  
Specific Inhibitor ◽  
Side Chain ◽  
Amino Acid Side Chain ◽  
Oseltamivir Carboxylate ◽  
Influenza A H1n1 ◽  
Binding Inhibition

ABSTRACT Oseltamivir carboxylate is a potent and specific inhibitor of influenza neuraminidase (NA). An influenza A/H1N1 variant selected in vitro with reduced susceptibility to oseltamivir carboxylate contains a His274Tyr mutation. To understand the mechanism by which a His274Tyr mutation gives rise to drug resistance, we studied a series of NA variant proteins containing various substitutions at position 274. Replacement of His274 with larger side chain residues (Tyr or Phe) reduced the NA sensitivity to oseltamivir carboxylate. In contrast, replacement of His274 with smaller side chain residues (Gly, Asn, Ser, and Gln) resulted in enhanced or unchanged sensitivity to oseltamivir carboxylate. Previous studies have suggested that the slow-binding inhibition of NA by oseltamivir carboxylate is a result of the reorientation of Glu276. Loss of this slow-binding inhibition in the His274Tyr and His274Phe mutant NA but not in His274Asn, His274Gly, His274Ser, or His274Gln supports the conclusion that the conformational change of Glu276 is restricted in the His274Tyr and His274Phe mutant NA upon oseltamivir carboxylate binding. Interestingly, His274Asn, as well as His274Gly, His274Ser, and His274Gln, also displayed reduced sensitivity to zanamivir and its analogue, 4-amino-Neu5Ac2en. Substitution of His274 with Tyr in influenza A/Tokyo/3/67 (H3N2) recombinant NA did not affect the susceptibility to oseltamivir carboxylate. These data indicate that the volume occupied by the amino acid side chain at position 274 can influence the sensitivities of influenza N1 NA but not of N2 NA to both oseltamivir carboxylate and zanamivir.

Effect of the basic amino-acid side chain length and the penultimate residue on the hydrolysis of benzoyldipeptides by carboxypeptidase B

1978 ◽  
Vol 56 (5) ◽  
pp. 315-318 ◽  
Author(s):  
Graham J. Moore ◽  
N. Leo Benoiton
Keyword(s):  
Amino Acid ◽  
Chain Length ◽  
Basic Amino Acid ◽  
Side Chain ◽  
Amino Acid Side Chain ◽  
Carboxypeptidase B ◽  
Side Chain Length ◽  
C Terminus ◽  
Guanidino Group ◽  
Hydrolysis Of

The kinetic parameters Km and kcat/Km have been determined for the carboxypeptidase B (CPB, EC 3.4.12.3) catalyzed hydrolysis of benzoylglycyl-DL-homolysine and benzoylglycyl-L-homoarginine. Plots of these data and those for Bz-Gly-Orn and Bz-Gly-Arg (Wolff, E. C., Schirmer, E. W. &Folk, J. E. (1962) J. Biol. Chem. 237, 3094–3099) and Bz-Gly-Lys versus the length of the side chain of the basic amino acid indicate that unlike trypsin (EC 3.4.21.4) (Seely, J. H. &Benoiton, N. L. (1970) Can. J. Biochem. 48, 1122–1131) CPB has a higher binding affinity for a guanidino group than for an amino group at the side chain of the substrate C-terminus. On the other hand, CPB is similar to trypsin (ibid) in that the best substrate would have a side chain length between those of lysine and arginine.Studies with Bz-MeGly-Lys and Bz-Ala-Lys showed that the former is very slowly hydrolyzed by CPB but that the latter is a good substrate, with a high affinity for the enzyme, indicative of considerable participation of the Cα-methyl group of alanine in the binding of the substrate to the enzyme.

scholarly journals The Stereochemistry of the Amino Acid Side Chain Influences the Inflammatory Potential of Muramyl Dipeptide in Experimental Meningitis

2003 ◽  
Vol 71 (6) ◽  
pp. 3663-3666 ◽  
Author(s):  
P. Cottagnoud ◽  
C. M. Gerber ◽  
P. A. Majcherczyk ◽  
F. Acosta ◽  
M. Cottagnoud ◽  
...  
Keyword(s):  
Amino Acid ◽  
Muramyl Dipeptide ◽  
Side Chain ◽  
Amino Acid Side Chain ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Peripheral Mononuclear Blood ◽  
Leukocyte Influx ◽  
Factor Alpha

ABSTRACT Intrathecal injections of 50 to 100 μg of (N-acetylmuramyl-l-alanyl-d-isoglutamine) muramyl dipeptide (MDP)/rabbit dose-dependently triggered tumor necrosis factor alpha (TNF-α) secretion (12 to 40,000 pg/ml) preceding the influx of leukocytes in the subarachnoid space of rabbits. Intrathecal instillation of heat-killed unencapsulated R6 pneumococci produced a comparable leukocyte influx but only a minimal level of preceding TNF-α secretion. The stereochemistry of the first amino acid (l-alanine) of the MDP played a crucial role with regard to its inflammatory potential. Isomers harboring d-alanine in first position did not induce TNF-α secretion and influx of leukocytes. This stereospecificity of MDPs was also confirmed by measuring TNF-α release from human peripheral mononuclear blood cells stimulated in vitro. These data show that the inflammatory potential of MDPs depends on the stereochemistry of the first amino acid of the peptide side chain and suggest that intact pneumococci and MDPs induce inflammation by different pathways.

Comparison of the Potency of 8-L-Arginine, 8-D-Arginine and 8-D-Homoarginine Vasopressin Analogs with Substituted Phenylalanine in Position 2

1994 ◽  
Vol 59 (6) ◽  
pp. 1439-1450 ◽  
Author(s):  
Miroslava Žertová ◽  
Jiřina Slaninová ◽  
Zdenko Procházka
Keyword(s):  
Amino Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Basic Amino Acid ◽  
The Other ◽  
Side Chain ◽  
Inhibitory Potency ◽  
Phase Synthesis ◽  
Other Hand ◽  
Order Of Magnitude

An analysis of the uterotonic potencies of all analogs having substituted L- or D-tyrosine or -phenylalanine in position 2 and L-arginine, D-arginine or D-homoarginine in position 8 was made. The series of analogs already published was completed by the solid phase synthesis of ten new analogs having L- or D-Phe, L- or D-Phe(2-Et), L- or D-Phe(2,4,6-triMe) or D-Tyr(Me) in position 2 and either L- or D-arginine in position 8. All newly synthesized analogs were found to be uterotonic inhibitors. Deamination increases both the agonistic and antagonistic potency. In the case of phenylalanine analogs the change of configuration from L to D in position 2 enhances the uterotonic inhibition for more than 1 order of magnitude. The L to D change in position 8 enhances the inhibitory potency negligibly. Prolongation of the side chain of the D-basic amino acid in position 8 seems to decrease slightly the inhibitory potency if there is L-substituted amino acid in position 2. On the other hand there is a tendency to the increase of the inhibitory potency if there is D-substituted amino acid in position 2.

Bcl-2 targeting siRNA expressed by a T7 vector system inhibits human tumor cell growth in vitro

2004 ◽  
Author(s):  
Lori Holle ◽  
Labri Hicks ◽  
Wendy Song ◽  
Eric Holle ◽  
Thomas Wagner ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Human Tumor ◽  
Vector System ◽  
Tumor Cell Growth ◽  
Human Tumor Cell
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