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Sonsoles Velázquez - One of the best experts on this subject based on the ideXlab platform.
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Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme.
European journal of medicinal chemistry, 2013Co-Authors: Alberto Diez-torrubia, Silvia Cabrera, Sonia De Castro, Carlos García-aparicio, Gwenn Mulder, Ingrid De Meester, María-josé Camarasa, Jan Balzarini, Sonsoles VelázquezAbstract:We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the Tetrapeptide Amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding Tetrapeptide Amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the Tetrapeptide Amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both Amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.
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Application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to different amine-containing drugs.
Journal of medicinal chemistry, 2010Co-Authors: Alberto Diez-torrubia, Silvia Cabrera, Carlos García-aparicio, Ingrid De Meester, María-josé Camarasa, Jan Balzarini, Sonsoles VelázquezAbstract:Here we explore the applicability of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to a variety of amine-containing drugs. Efficient procedures have been developed for the synthesis of dipeptide and Tetrapeptide Amide prodrugs including N-acylation protocols of the exocyclic amino function of cytidine and adenosine nucleosides. Our studies demonstrated that XaaPro dipeptides linked to a free amino group present on an aromatic ring or on a sugar entity are prodrugs that efficiently release the parent drug upon conversion by purified DPPIV/CD26 as well as soluble DPPIV/CD26 in bovine and human serum. Vildagliptin, a specific inhibitor of DPPIV/CD26, was able to completely block the hydrolysis of the prodrugs in the presence of purified CD26 but also in human and bovine serum. When the amino group is present on a pyrimidine or purine ring, the dipeptide derivatives are chemically unstable, whereas the Tetrapeptide derivatives (i.e., ValProValPro or ValAlaValPro) were much more stable in solution and efficiently converted to the parent drug by the action of DPPIV/CD26. This DPPIV/CD26-directed prodrug technology can be useful to increase solubility of the parent drug molecules and/or to allow better formulation properties.
Claudio Toniolo - One of the best experts on this subject based on the ideXlab platform.
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Factors governing 310-Helix vs α-helix formation in peptides: Percentage of cα-tetrasubstituted α-amino acid residues and sequence dependence
Biopolymers, 2002Co-Authors: Marco Crisma, Fernando Formaggio, William Bisson, Quirinus B. Broxterman, Claudio TonioloAbstract:As an additional step toward the dissection of the factors responsible for the onset of 3(10)-helix vs alpha-helix in peptides, in this paper we describe the results of a three-dimensional (3D) structural analysis by x-ray diffraction of the N(alpha)-acylated heptapeptide alkylAmide mBrBz-L-Iva-L-(alphaMe)Val-L-Abu-L-(alphaMe)Val-L-(alphaMe)Phe-L-(alphaMe)Val-L-Iva-NHMe characterized by a single (L-Abu3) C(alpha)-trisubstituted and six C(alpha)-tetrasubstituted alpha-amino acids. We find that in the crystal state this peptide is folded in a mixed helical structure with short elements of 3(10)-helix at either terminus and a central region of alpha-helix. This finding, taken together with the published NMR and x-ray diffraction data on the all C(alpha)-methylated parent sequence and its L-Val2 analog (also the latter heptapeptide has a single C(alpha)-trisubstituted alpha-amino acid) strongly supports the view that one C(alpha)-trisubstituted alpha-amino acid inserted near the N-terminus of an N(alpha)-acylated heptapeptide alkylAmide sequence may be enough to switch a regular 3(10)-helix into an essentially alpha-helical conformation. As a corollary of this work, the x-ray diffraction structure of the N(alpha)-protected, C-terminal Tetrapeptide alkylAmide Z-L-(alphaMe)Val-L-(alphaMe)Phe-L-(alphaMe)Val-L-Iva-NHMe, also reported here, is clearly indicative of the preference of this fully C(alpha)-methylated, short peptide for the 3(10)-helix. As the same terminally blocked sequence is mixed 3(10)/alpha-helical in the L-Abu3 heptapeptide Amide but regular 3(10)-helical in the Tetrapeptide Amide and in the parent heptapeptide Amide, these results point to an evident plasticity even of a fully C(alpha)-methylated short peptide.
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Folding versatility of the C-terminal Tetrapeptide Amide sequence of the lipopeptaibol antibiotics trichodecenin and trichogin
Letters in Peptide Science, 1996Co-Authors: Marco Crisma, Giovanni Valle, Fernando Formaggio, Vania Monaco, Claudio TonioloAbstract:An X-ray diffraction analysis of Z - l -Leu-Aib-Gly- l -Ile- l -Leu-OMe, containing the N^α-acylated Tetrapeptide Amide sequence- l -Leu-Aib-Gly- l -Ile-, showed that in the crystal state the carbonyl group preceding the l -Leu^1 residue acts as the acceptor of two C=O⋯H−N intramolecular H-bonds, which give rise to an- l -Leu^1-Aib^2-type-III' β-turn and an- l -Leu^1-Aib^2-Gly^3- l -Ile^4-π-turn, respectively. A second (type-I') β-turn encompasses the-Aib^2-Gly^3-sequence. This is the third type of folding motif known for that Tetrapeptide sequence, considering also those already published for the C-terminal segment of the lipopeptaibol antibiotics trichodecenin I and trichogin A IV.
Luis Moroder - One of the best experts on this subject based on the ideXlab platform.
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Peptide/benzodiazepine hybrids as ligands of CCKA and CCKB receptors
Biopolymers, 2000Co-Authors: Achim Escherich, Chantal Escrieut, Daniel Fourmy, Jrgen Lutz, A. Stephanie Van Neuren, Gerhard Mller, Andrea Schafferhans, Gerhard Klebe, Luis MoroderAbstract:The (neuro)hormones gastrin and cholecystokinin (CCK) share a common C-terminal Tetrapeptide Amide sequence that has been recognized as the message portion while the N-terminal extensions are responsible for the CCKA and CCKB receptor subtype selectivity and avidity. 1,4-Benzodiazepine derivatives are potent and selective antagonists of these receptors, and according to comparative molecular field analysis, the structures of these nonpeptidic compounds could well mimic the message sequence of the peptide agonists at least in terms of spatial array of the aromatic residues. Docking of a larger series of low molecular weight nonpeptide antagonists to a homology modeling derived CCKB receptor structure revealed a consensus binding mode that is further validated by data from site-directed mutagenesis studies of the receptors. Whether this putative binding pocket of the nonpeptide antagonists is identical to that of the message portion of the peptide agonists, or whether it is distinct and spatially separated, or overlapping, but with distinct interaction sites, is still object of debate. Using a 1,4-benzodiazepine core amino-functionalized at the C3 position, related tryptophanyl derivatives were synthesized as mimics of the Tetrapeptide and subsequently extended N-terminally with gastrin and CCK address sequences. All hybrid constructs were recognized as antagonists by the CCKA and CCKB receptors, but their address portions were uncapable of enhancing in significant manner selectivity and avidity. Consequently, the binding of the peptide/benzodiazepine hybrids has to be dictated mainly by the benzodiazepine moiety, which apparently prevents optimal interactions of the address peptides with extracellular receptor subdomains. These findings would strongly support the view of distinct binding sites for the message portion of the peptide agonists and the benzodiazepine-based nonpeptide antagonists. © 2001 John Wiley & Sons, Inc. Biopolymers 56: 55–76, 2001
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Cyclodextrin as Carrier of Peptide Hormones. Conformational and Biological Properties of β-Cyclodextrin/Gastrin Constructs
Journal of the American Chemical Society, 1998Co-Authors: Norbert Schaschke, Stella Fiori, Elisabeth Weyher, Chantal Escrieut, Daniel Fourmy, Gerhard Müller, Luis MoroderAbstract:The C-terminal Tetrapeptide Amide of gastrin, the shortest sequence of this gastrointestinal hormone capable of exhibiting all the biological properties even though at reduced potency, and the rela...
Jean Martinez - One of the best experts on this subject based on the ideXlab platform.
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Biological effects of human gastrin I and II chemically modified at the C-terminal Tetrapeptide Amide.
Peptides, 1992Co-Authors: Pierre Fulcrand, Jean-pierre Bali, Marc Rodriguez, Richard Magous, Jeanine Laur, Jean MartinezAbstract:Abstract Binding to gastrin receptors and gastric acid secretion experiments were performed with gastrin derivatives modified at the C- terminal Tetrapeptide Amide from HG-13 sequence. 1. When the ultimate phenylalanine Amide was replaced by a phenethylester or a phenetylAmide moiety, the resulting compound bound to gastrin receptors ( K d ≈ 10 nM ) and exhibited antagonist activity on gastrin-induced acid secretion in the anesthetized rat. 2. Changing the peptide bond between Trp and Leu residues to a -Ψ(CH 2 -NH)- bond resulted in a compound which also bound to gastrin receptors ( K d ≈ 10 n M ) but presented agonist activity on acid secretion in the rat. In contrast, when the peptide bond between Leu and Asp residues was replaced by a -Ψ(CH 2 -NH)- bond, the resulting compound was devoid of any affinity for gastrin receptor ( K d > 10 −6 M ) and of any biological activity. 3. The HG-13 derivatives were synthesized in sulfated and unsulfated forms: O-sulfation of the HG-13 tyrosine residue did not change its intrinsic in vivo activity but enhanced its affinity for gastrin receptors ( K d ≈ 0.3 n M ). On the contrary, O-sulfation of the various chemically modified HG-13 had no significant effect in either in vitro or in vivo experiments. 4. Finally, no significant difference between binding on parietal (F3) and nonparietal (F1) cells was observed, in agreement with the presence of a gastrin-type receptor in these two cell populations.
Alberto Diez-torrubia - One of the best experts on this subject based on the ideXlab platform.
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Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme.
European journal of medicinal chemistry, 2013Co-Authors: Alberto Diez-torrubia, Silvia Cabrera, Sonia De Castro, Carlos García-aparicio, Gwenn Mulder, Ingrid De Meester, María-josé Camarasa, Jan Balzarini, Sonsoles VelázquezAbstract:We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the Tetrapeptide Amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding Tetrapeptide Amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the Tetrapeptide Amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both Amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.
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Application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to different amine-containing drugs.
Journal of medicinal chemistry, 2010Co-Authors: Alberto Diez-torrubia, Silvia Cabrera, Carlos García-aparicio, Ingrid De Meester, María-josé Camarasa, Jan Balzarini, Sonsoles VelázquezAbstract:Here we explore the applicability of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to a variety of amine-containing drugs. Efficient procedures have been developed for the synthesis of dipeptide and Tetrapeptide Amide prodrugs including N-acylation protocols of the exocyclic amino function of cytidine and adenosine nucleosides. Our studies demonstrated that XaaPro dipeptides linked to a free amino group present on an aromatic ring or on a sugar entity are prodrugs that efficiently release the parent drug upon conversion by purified DPPIV/CD26 as well as soluble DPPIV/CD26 in bovine and human serum. Vildagliptin, a specific inhibitor of DPPIV/CD26, was able to completely block the hydrolysis of the prodrugs in the presence of purified CD26 but also in human and bovine serum. When the amino group is present on a pyrimidine or purine ring, the dipeptide derivatives are chemically unstable, whereas the Tetrapeptide derivatives (i.e., ValProValPro or ValAlaValPro) were much more stable in solution and efficiently converted to the parent drug by the action of DPPIV/CD26. This DPPIV/CD26-directed prodrug technology can be useful to increase solubility of the parent drug molecules and/or to allow better formulation properties.