Biomedical subjects

Nicolas Floquet

Publications and source records attributed to Nicolas Floquet.

7 recordsLinked to original sources

PubMed2006

Normal mode analysis as a prerequisite for drug design: application to matrix metalloproteinases inhibitors.

We demonstrate the utility of normal mode analysis in correctly predicting the binding modes of inhibitors in the active sites of matrix metalloproteinases (MMPs). We show the accuracy in predicting the positions of MMP-3 inhibitors is strongly dependent on which structure is used as the target, especially when it has been energy minimized. This dependency can be overcome by using intermediate structures generated along one of the normal modes previously calculated for a given target. These results may be of prime importance for further in silico drug discovery.

Drug Design↗

PubMed2006

Structural and antitumor properties of the YSNSG cyclopeptide derived from tumstatin.

We previously demonstrated that the NC1[alpha3(IV)185-191] CNYYSNS peptide inhibited in vivo tumor progression. The YSNS motif formed a beta turn crucial for biological activity. The aim of the present study was to design a YSNSG cyclopeptide with a constrained beta turn on the YSNS residues more stable than CNYYSNS. By nuclear magnetic resonance and molecular modeling, we demonstrated that the YSNSG cyclopeptide actually adopted the expected beta-turn conformation. It promoted melanoma cell adhesion and prevented their adhesion to the native peptide. It inhibited in vitro cell proliferation and migration through Matrigel by downregulating proteolytic cascades. Moreover, intraperitoneal administration of the YSNSG cyclopeptide inhibited melanoma progression far more efficiently than the native peptide. The increased solubility and stability at low pH of the YSNSG cyclopeptide suggest this peptide as a potent antitumor therapeutic agent.

Animals↗

PubMed2005

Structure and modeling studies of the carboxy-terminus region of human tropoelastin.

Elastin macromolecular assembly is a highly complex mechanism involving many steps including coacervation, cross-linking, and probably other (not known) phenomena. In past studies, it has been proposed that the C-terminal part of tropoelastin is also involved in this process and may play a key role in tropoelastin interactions with other proteins of the final elastic fibres scaffold. Presented here are the results of the biophysical studies (biospectroscopy, bioinformatics) of the C-terminal domain of tropoelastin. We report the detailed structures adopted by the oxidized (native) and reduced forms of the free synthetic peptide with sequence encoded by exon 36 of human tropoelastin (GGACLGKACGRKRK) and propose a dynamical interpretation of which structures may be involved in interactions with other extra-cellular matrix proteins. We also suggest that these structures may be retrieved in other proteins sharing a consensus sequence; however no definitive conclusion can be drawn here on a possible structure-function relationship.

Amino Acid Sequence↗

PubMed2004

Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide.

The elastic properties of elastin have essentially been discussed in terms of dominant entropic components, with questions still remaining about whether the basic mechanism is compatible with the classical theory of rubber elasticity. A better understanding of the structure-function relationships in terms of the protein's elastic properties remains an important goal in elastin science. Recently, we succeeded in the exon-by-exon synthesis of all polypeptide sequences encoded by the so-called hydrophobic exons and almost all of the cross-linking exons of human tropoelastin. Among these, the peptide encoded by exon 5 (PGGLAGAGLGA) has been extensively studied by classical spectroscopic methods, such as CD and NMR spectroscopy, and by molecular dynamics simulations. The results obtained clearly evidenced a large flexibility of the polypeptide chain, which oscillates between rather extended conformations, such as PPII, and folded ones, such as beta turns. At the supramolecular level, we obtained evidence by TEM that shows that the peptide encoded by exon 5 is able to self-assemble in fibrillar structures, a result indicating that the "information" for self-assembly is also contained within a small domain of tropoelastin.

Amino Acid Sequence↗

PubMed2004

Structural characterization of VGVAPG, an elastin-derived peptide.

Elastic fibers are an important component of the extracellular matrix, providing elasticity and resilience to tissues that require the ability to deform repetitively and reversibly. Among the elastin-derived peptides, the Val-Gly-Val-Ala-Pro-Gly (VGVAPG) hexapeptide is known for its chemotactic activity and metalloproteinases upregulation properties. As other elastin-derived peptides, having homologous similar sequences, do not exhibit any biological activity, the following question arises: Does the peptide-receptor interaction need a specific active conformation? Previous experimental studies including NMR and CD spectroscopies did not clearly identify the conformations adopted by the VGVAPG peptide in solution. However, structural predictions made on VGVAPG and related XGXXPG peptides suggested a folded beta-turn conformation. So we undertook a theoretical and experimental study of the VGVAPG peptide. The work presented here, which gives an overall structural description of VGVAPG behavior in water, also provides an additional insight into its structure-activity relationship. Both theoretical and experimental results suggest the existence of an ensemble of rather extended and folded conformations in solution. All the folded structures obtained exhibit a type VIII beta-turn spanning the GVAP sequence. In the lack of any structural information concerning the elastin receptor, these results suggest that such a conformation could be relevant for the peptide-receptor interaction and thus for biological activity.

Elastin↗

PubMed2004

Elastin as a matrikine.

The fact that elastin peptides, the degradation products of the extracellular matrix protein elastin, are chemotactic for numerous cell types, promote cell cycle progression and induce release of proteolytic enzymes by stromal and cancer cells, strongly suggests that their presence in tissues could contribute to tumour progression. Thus, elastin peptides qualify as matrikines, i.e. peptides originating from the fragmentation of matrix proteins and presenting biological activities. After a brief description of their origin, the biological activities of these peptides are reviewed, emphasising their potential role in cancer. The nature of their receptor and the signalling events it controls are also discussed. Finally, the structural selectivity of the elastin complex receptor is presented, leading to the concept of elastokine (matrikine originating from elastin fragmentation) and morpho-elastokine, i.e. peptides presenting a conformation similar to that of bioactive elastin peptides and mimicking their effects.

Elastin↗

PubMed2003

The antitumor properties of the alpha3(IV)-(185-203) peptide from the NC1 domain of type IV collagen (tumstatin) are conformation-dependent.

Tumor progression may be controlled by various fragments derived from noncollagenous 1 (NC1) C-terminal domains of type IV collagen. We demonstrated previously that a peptide sequence from the NC1 domain of the alpha3(IV) collagen chain inhibits the in vitro expression of matrix metalloproteinases in human melanoma cells through RGD-independent binding to alpha(v)beta(3) integrin. In the present paper, we demonstrate that in a mouse melanoma model, the NC1 alpha3(IV)-(185-203) peptide inhibits in vivo tumor growth in a conformation-dependent manner. The decrease of tumor growth is the result of an inhibition of cell proliferation and a decrease of cell invasive properties by down-regulation of proteolytic cascades, mainly matrix metalloproteinases and the plasminogen activation system. A shorter peptide comprising the seven N-terminal residues 185-191 (CNYYSNS) shares the same inhibitory profile. The three-dimensional structures of the CNYYSNS and NC1 alpha3(IV)-(185-203) peptides show a beta-turn at the YSNS (188-191) sequence level, which is crucial for biological activity. As well, the homologous MNYYSNS heptapeptide keeps the beta-turn and the inhibitory activity. In contrast, the DNYYSNS heptapeptide, which does not form the beta-turn at the YSNS level, is devoid of inhibitory activity. Structural studies indicate a strong structure-function relationship of the peptides and point to the YSNS turn as necessary for biological activity. These peptides could act as potent and specific antitumor antagonists of alpha(v)beta(3) integrin in melanoma progression.

Amino Acid Sequence↗