Biomedical subjects

Patrick Chène

Publications and source records attributed to Patrick Chène.

11 recordsLinked to original sources

PubMed2006

Study of the ATP-binding site of helicase IV from Escherichia coli.

Helicases contain conserved motifs involved in ATP/magnesium/nucleic acid binding and in the mechanisms coupling nucleotide hydrolysis to duplex unwinding. None of these motifs are located at the adenine-binding pocket of the protein. We show here that the superfamily I helicase, helicase IV from Escherichia coli, utilizes a conserved glutamine and conserved aromatic residue to interact with ATP. Other superfamily I helicases such as, UvrD/Rep/PcrA also possess these residues but in addition they interact with adenine via a conserved arginine, which is replaced by a serine in helicase IV. Mutation of this serine residue in helicase IV into histidine or methionine leads to proteins with unaffected ATPase and DNA-binding activities but with low helicase activity. This suggests that residues located at the adenine-binding pocket, in addition to be involved in ATP-binding, are important for efficient coupling between ATP hydrolysis and DNA unwinding.

Adenine↗

PubMed2006

Drugs targeting protein-protein interactions.

Most biological processes involve permanent and nonpermanent interactions between different proteins, and many protein complexes play a key role in various human diseases. Therefore, molecules that prevent the formation of these protein complexes could be valuable new therapeutic agents to treat these diseases. Protein interfaces have not evolved to bind low-molecular-weight molecules, as is the case with enzyme catalytic sites. It is therefore difficult to identify small compounds that inhibit protein-protein interactions. However, there is considerable diversity in the structure of protein interfaces, some of which may be more attractive than others for medicinal chemistry. One of the main challenges in drug discovery is to identify these interfaces and to exploit their properties to make marketable drugs. Herein, the properties of protein interfaces are discussed in light of their use as drug targets.

Amino Acid Sequence↗

PubMed2005

Inhibition of DNA helicases with DNA-competitive inhibitors.

Helicases form an attractive protein family for drug discovery because they are involved in various human diseases. In this report, we show that it is possible to inhibit both the ATPase and the helicase activities of a DNA helicase with dibenzothiepins that bind at its nucleic acid binding site. These results suggest a drug discovery strategy to inhibit DNA helicases.

Adenosine Triphosphatases↗

PubMed2004

Inhibition of the p53-hdm2 interaction with low molecular weight compounds.

The hdm2 protein, upon binding to p53, inhibits its tumor suppressor activity. The inhibition of the p53-hdm2 interaction represents therefore a new therapeutic strategy to activate wild type p53 in tumors. Potent low molecular weight compounds inhibiting this protein-protein interaction, which are active in vivo, have just been identified. This offers new perspectives and hopes in this research area.

Animals↗

PubMed2004

Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface.

MDM2 inhibits p53 transcriptional activity, favors its nuclear export, and stimulates its degradation. Inhibition of the p53-MDM2 interaction with synthetic molecules should therefore lead to both the nuclear accumulation and the activation of p53 followed by the death of the tumor cells from apoptosis. Inhibitors of the p53-MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type p53 in tumors. This review describes our current knowledge on the properties of the existing p53-MDM2 antagonists. Because the discovery of modulators of protein-protein interactions is an emerging field in drug discovery, the strategy used for designing inhibitors of the p53-MDM2 interaction could serve as an example for other protein interfaces.

Animals↗

PubMed2003

Inhibiting the p53-MDM2 interaction: an important target for cancer therapy.

p53 is an attractive therapeutic target in oncology because its tumour-suppressor activity can be stimulated to eradicate tumour cells. Inhibiting the p53-MDM2 interaction is a promising approach for activating p53, because this association is well characterized at the structural and biological levels. MDM2 inhibits p53 transcriptional activity, favours its nuclear export and stimulates its degradation, so inhibiting the p53-MDM2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p53-positive stressed cells.

Active Transport, Cell Nucleus↗

PubMed2003

The ATPases: a new family for a family-based drug design approach.

The rapid discovery of new drugs is greatly facilitated when a family of related proteins is targeted with a similar approach in chemistry. Few protein families have so far been investigated using this kind of 'family-based' approach. Therefore, to increase the size of our Pharmacopeia and to cure human diseases more efficiently, new druggable protein families must be identified. It is shown in this review that ATPases are very good candidates for a family-based approach. The human proteome contains many ATPases, which are involved in several diseases. All the ATPases contain a nucleotide-binding site, and it is therefore possible to target all of them with a single strategy in chemistry; the design of competitive ATP inhibitors. Moreover, because a similar approach has been conducted with the protein kinases, the compound libraries and the knowledge developed in the kinase field can be directly applied to the ATPases.

ATP-Binding Cassette Transporters↗

PubMed2002

The gain of function of the p53 mutant Asp281Gly is dependent on its ability to form tetramers.

The influence of tetramerisation on the properties of the p53 mutants is poorly understood. We describe here the influence of the tetramerisation on the properties of the oncogenic mutant Asp281Gly. We show that despite being both nuclear the tetrameric Asp281Gly and the monomeric Asp281GlyLeu344Pro proteins have different properties: only Asp281Gly stimulates the transcription of the multidrug resistance-1 gene promoter and induces cisplatin resistance in Saos-2 cells. Moreover, we identify a 130-kDa protein that specifically interacts with Asp281Gly but not with Asp281GlyLeu344Pro. This suggests that tetramerisation is important for the properties of the p53 mutants and that these properties might be mediated via protein-protein interactions.

Antineoplastic Agents↗

PubMed2002

Study of the cytotoxic effect of a peptidic inhibitor of the p53-hdm2 interaction in tumor cells.

Inhibitors of the p53-hdm2 interaction are attractive molecules for stimulating the p53 pathway in tumors. In this report, an inhibitor of the p53-hdm2 interaction, the AP peptide, is used to activate p53 in tumor cells expressing various levels of hdm2 protein. It induces apoptosis only in cells expressing high endogenous levels of hdm2 protein. The absence of apoptosis in tumor cells with low hdm2 levels is due not to alterations in the p53-dependent apoptotic pathway but to a different regulation of this pathway. The peptide is also less toxic for non-tumor cells than for tumor cells overexpressing the hdm2 protein.

Apoptosis↗

PubMed2002

Aib-based peptide backbone as scaffolds for helical peptide mimics.

Helical peptides that can intervene and disrupt therapeutically important protein-protein interactions are attractive drug targets. In order to develop a general strategy for developing such helical peptide mimics, we have studied the effect of incorporating alpha-amino isobutyric acid (Aib), an amino acid with strong preference for helical backbone, as the sole helix promoter in designed peptides. Specifically, we focus on the hdm2-p53 interaction, which is central to development of many types of cancer. The peptide corresponding to the hdm2 interacting part of p53, helical in bound state but devoid of structure in solution, served as the starting point for peptide design that involved replacement of noninteracting residues by Aib. Incorporation of Aib, while preserving the interacting residues, led to significant increase in helical structure, particularly at the C-terminal region as judged by nuclear magnetic resonance and circular dichroism. The interaction with hdm2 was also found to be enhanced. Most interestingly, trypsin cleavage was found to be retarded by several orders of magnitude. We conclude that incorporation of Aib is a feasible strategy to create peptide helical mimics with enhanced receptor binding and lower protease cleavage rate.

Amino Acid Sequence↗

PubMed2002

ATPases as drug targets: learning from their structure.

ATPases are involved in several cellular functions, and are at the origin of various human diseases. They are therefore attractive drug targets, and various ATPase inhibitors are already on the market. However, most of these drugs are active without binding directly to the nucleotide-binding site. An alternative strategy to inhibit ATPases is to design competitive ATP inhibitors. This approach, which has been used successfully to design protein-kinase inhibitors, depends on the structure of the nucleotide-binding site. This review describes the structural features of the nucleotide-binding site of various ATPases and analyses how this structural information can be exploited for drug discovery.

Adenosine Triphosphatases↗