Horst Kessler - Academia.edu (original) (raw)

Papers by Horst Kessler

Research paper thumbnail of Konformationsanalyse von Aminos�ure-Seitenketten in Peptiden durch quantitative Auswertung von Cross-Peaks in COLOC-Spektren

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Research paper thumbnail of Automated backbone assignment of labeled proteins using the threshold accepting algorithm

Journal of biomolecular NMR, 1998

The sequential assignment of backbone resonances is the first step in the structure determination... more The sequential assignment of backbone resonances is the first step in the structure determination of proteins by heteronuclear NMR. For larger proteins, an assignment strategy based on proton side-chain information is no longer suitable for the use in an automated procedure. Our program PASTA (Protein ASsignment by Threshold Accepting) is therefore designed to partially or fully automate the sequential assignment of proteins, based on the analysis of NMR backbone resonances plus C beta information. In order to overcome the problems caused by peak overlap and missing signals in an automated assignment process, PASTA uses threshold accepting, a combinatorial optimization strategy, which is superior to simulated annealing due to generally faster convergence and better solutions. The reliability of this algorithm is shown by reproducing the complete sequential backbone assignment of several proteins from published NMR data. The robustness of the algorithm against misassigned signals, no...

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Research paper thumbnail of Hsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules

Nature communications, 2015

The cochaperone Sti1/Hop physically links Hsp70 and Hsp90. The protein exhibits one binding site ... more The cochaperone Sti1/Hop physically links Hsp70 and Hsp90. The protein exhibits one binding site for Hsp90 (TPR2A) and two binding sites for Hsp70 (TPR1 and TPR2B). How these sites are used remained enigmatic. Here we show that Sti1 is a dynamic, elongated protein that consists of a flexible N-terminal module, a long linker and a rigid C-terminal module. Binding of Hsp90 and Hsp70 regulates the Sti1 conformation with Hsp90 binding determining with which site Hsp70 interacts. Without Hsp90, Sti1 is more compact and TPR2B is the high-affinity interaction site for Hsp70. In the presence of Hsp90, Hsp70 shifts its preference. The linker connecting the two modules is crucial for the interaction with Hsp70 and for client activation in vivo. Our results suggest that the interaction of Hsp70 with Sti1 is tightly regulated by Hsp90 to assure transfer of Hsp70 between the modules, as a prerequisite for the efficient client handover.

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Research paper thumbnail of Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging

Theranostics, 2015

Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular traffi... more Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [(68)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [(68)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [(68)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/C...

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Research paper thumbnail of Spectroscopically well-characterized RGD optical probe as a prerequisite for lifetime-gated tumor imaging

Molecular imaging, 2011

Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive im... more Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive imaging of tumors overexpressing ανβ3 integrins. An important prerequisite for optimum detection sensitivity in vivo is strongly absorbing and highly emissive probes with a known fluorescence lifetime. The RGD-Cy5.5 optical probe was derived by coupling Cy5.5 to a cyclic arginine-glycine-aspartic acid-d-phenylalanine-lysine (RGDfK) peptide via an aminohexanoic acid spacer. Spectroscopic properties of the probe were studied in different matrices in comparison to Cy5.5. For in vivo imaging, human glioblastoma cells were subcutaneously implanted into nude mice, and in vivo fluorescence intensity and lifetime were measured. The fluorescence quantum yield and lifetime of Cy5.5 were found to be barely affected on RGD conjugation but dramatically changed in the presence of proteins. By time domain fluorescence imaging, we demonstrated specific binding of RGD-Cy5.5 to glioblastoma xenografts in nu...

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Research paper thumbnail of A Spin System Labeled and Highly Resolved ed-H(CCO)NH-TOCSY Experiment for the Facilitated Assignment of Proton Side Chains in Partially Deuterated Samples

Journal of biomolecular NMR, 1998

The introduction of deuterated and partially deuterated protein samples has greatly facilitated t... more The introduction of deuterated and partially deuterated protein samples has greatly facilitated the 13C assignment of larger proteins. Here we present a new version of the HC(CO)NH-TOCSY experiment, the ed-H(CCO)NH-TOCSY experiment for partially deuterated samples, introducing a multi-quantum proton evolution period. This approach removes the main relaxation source (the dipolar coupling to the directly bound 13C spin) and leads to a significant reduction of the proton and carbon relaxation rates. Thus, the indirect proton dimension can be acquired with high resolution, combined with a phase labeling of the proton resonances according to the C-C spin system topology. This editing scheme, independent of the CHn multiplicity, allows to distinguish between proton side-chain positions occurring within a narrow chemical shift range. Therefore this new experiment facilitates the assignment of the proton chemical shifts of partially deuterated samples even of high molecular weights, as demo...

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Research paper thumbnail of Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2001

The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. ... more The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the alpha(v)beta3 integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed alpha(v)beta3-selective tumor uptake. However, these first-generation compounds predominantly revealed hepatobiliary excretion with high radioactivity found in the liver. In this report, the synthesis and biological evaluation of the first glycosylated RGD-containing peptide (RGD-peptide) for the noninvasive imaging of alpha(v)beta3 expression are described. Peptides were assembled on a solid support using fluorenylmethoxycarbonyl-coupling protocols. The precursor cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP1 was synthesized by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-beta-D-glycero-D-gulo-heptonic acid (SAA(Bn3)) with cyclo(-Arg(Mtr)-Gly-Asp(OtBu)-D-Tyr(tB...

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Research paper thumbnail of Calculating three-dimensional molecular structure from atom-atom distance information: cyclosporin A

International journal of peptide and protein research, 1989

In recent years methods for deriving spatial molecular structure from atom-atom distance informat... more In recent years methods for deriving spatial molecular structure from atom-atom distance information have gained in importance due to the emergence of two-dimensional nuclear magnetic resonance (n.m.r) techniques, which make it possible to obtain such distance information for polypeptides, small proteins, sugars, and DNA fragments in solution. Distance geometry (DG) and restrained molecular dynamics (MD) refinement are applied to a cyclic polypeptide, the immunosuppressive drug cyclosporin A, and the results are compared. Two different procedures, DG followed by restrained MD, and straightforward restrained MD starting from the X-ray structure, both lead to a unique conformation that satisfies the 58 experimentally determined distance constraints. The results nicely show the relative merits of DG and restrained MD techniques for determining spatial molecular structure from distance information.

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Research paper thumbnail of Improvement of drug-like properties of peptides: the somatostatin paradigm

Expert Opinion on Drug Discovery, 2010

Peptides are promising candidates as therapeutic agents due to their wide involvement in physiolo... more Peptides are promising candidates as therapeutic agents due to their wide involvement in physiological processes. However, their often non-selective activity and their poor drug-like properties, mainly their inherent low stability to enzymatic degradation and poor oral bioavailability, limit their clinical potential. Somatostatin is a peptide hormone involved in many different biological functions. The role of its five different receptor subtypes and their interplay in medicinal processes is only partially understood. In addition, it suffers from poor drug-like properties. We review several promising chemical modifications, including head-to-tail and backbone cyclization as well as N-methylation, which were applied throughout the years in the development of various somatostatin analogs. These modifications led to enhanced metabolic stability and intestinal permeability. In addition, several analogs exhibited specific receptor subtype activation. The results presented in this review suggest a potential use of these chemical modifications in order to achieve required characteristics for a bioactive peptide, mainly for clinical usage.

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Research paper thumbnail of Mimicking bone extracellular matrix: Integrin-binding peptidomimetics enhance osteoblast-like cells adhesion, proliferation, and differentiation on titanium

Colloids and Surfaces B: Biointerfaces, 2015

Interaction between the surface of implants and biological tissues is a key aspect of biomaterial... more Interaction between the surface of implants and biological tissues is a key aspect of biomaterials research. Apart from fulfilling the non-toxicity and structural requirements, synthetic materials are asked to direct cell response, offering engineered cues that provide specific instructions to cells. This work explores the functionalization of titanium with integrin-binding peptidomimetics as a novel and powerful strategy to improve the adhesion, proliferation and differentiation of osteoblast-like cells to implant materials. Such biomimetic strategy aims at targeting integrins αvβ3 and α5β1, which are highly expressed on osteoblasts and are essential for many fundamental functions in bone tissue development. The successful grafting of the bioactive molecules on titanium is proven by contact angle measurements, X-ray photoelectron spectroscopy and fluorescent labeling. Early attachment and spreading of cells are statistically enhanced by both peptidomimetics compared to unmodified titanium, reaching values of cell adhesion comparable to those obtained with full-length extracellular matrix proteins. Moreover, an increase in alkaline phosphatase activity, and statistically higher cell proliferation and mineralization are observed on surfaces coated with the peptidomimetics. This study shows an unprecedented biological activity for low-molecular-weight ligands on titanium, and gives striking evidence of the potential of these molecules to foster bone regeneration on implant materials.

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Research paper thumbnail of Human Integrin αvβ5:  Homology Modeling and Ligand Binding

Journal of Medicinal Chemistry, 2004

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Research paper thumbnail of New perspective in peptide chemistry by N-alkylation

Advances in experimental medicine and biology, 2009

Introduction Oral bioavailability is a major concern in the development of peptide based drugs. P... more Introduction Oral bioavailability is a major concern in the development of peptide based drugs. Peptides usually possess high selectivity and potency but the major drawback in their development as a drug is the extremely low oral availability. Insufficient bioavailability of ...

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Research paper thumbnail of A new strategy for the synthesis of cyclopeptides containing diaminoglutaric acid

A new synthesis of orthogonally protected diaminoglutaric acid containing peptides using the Ugi ... more A new synthesis of orthogonally protected diaminoglutaric acid containing peptides using the Ugi four component condensation is presented. To demonstrate that this method is useful to replace cystine by diaminoglutaric acid in biologically interesting peptides, we built up two cyclic somatostatin analogues deriving from Sandostatin and from TT-232. A photolytically cleavable amine derivative of the nitroveratryl type is used for the Ugi four component condensation. Because of a racemic build up of the new stereocentre of the diaminoglutaric acid, and racemization of the isonitrile component, four diastereomeric peptides resulted that were separated by HPLC. The stereochemistry of the cyclopeptides could be easily and unambiguously assigned by chiral gas chromatography and a reference sample of enantiomerically pure (2S,4S)-diaminoglutaric acid.

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Research paper thumbnail of NOESY‐TOCSY, an Advantageous 2D NMR Technique for the Analysis of Peptide Sequences

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Research paper thumbnail of Prevention of phalloidin-induced lesions on isolated rat hepatocytes by novel synthetic analogues of somatostatin

Exposure of freshly isolated hepatocytes to phalloidin produced blebs on their surfaces: this phe... more Exposure of freshly isolated hepatocytes to phalloidin produced blebs on their surfaces: this phenomenon was time- and dose-dependent and irreversible. When hepatocytes were pretreated with somatostatin or with some of its synthetic analogues, formation of blebs was dramatically reduced. This cytoprotective effect was dose-dependent: the dose-response profiles enabled the determination of the CD50 values, i.e., the concentrations of analogues that yielded 50% cytoprotection. The analogues with sequences of amino acids in the retro form, compared to those in somatostatin-14, exhibited higher cytoprotection; the retro hexapeptide, cyclo(-Phe-Thr-Lys-D-Trp-Phe-D-Pro-), was 27 times more active than somatostatin-14. Specificity of cytoprotection was examined by pretreating hepatocytes with biologically active peptide hormones prior to exposure to phalloidin. On a molar basis, prolactin and thyroid-stimulating hormone possessed activity comparable to that of somatostatin-14, whereas glucagon was twice as active. Insulin, vitamin A and propranolol exercised less than 10% protection. The synthetic analogues of somatostatin are potent protective agents against cell lesions induced by phalloidin. Formation of blebs on hepatocytes by toxins and their prevention by agents of interest may serve as a suitable morphological assay for screening of cytotoxicity and cytoprotection.

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Research paper thumbnail of Selection of methyl resonances in proton-detected heteronuclear shift correlation, the HQQC experiment

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Research paper thumbnail of Increased resolution in proton detected heteronuclear NMR experiments by folding in the hetero‐dimension

ABSTRACT

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Research paper thumbnail of NMR spectroscopic studies on kinetics and thermodynamics of reversible dissociation reactions. 6. Ionization of tropylium azide in liquid sulfur dioxide and selective migration of the azide ligand in less polar solvents

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Research paper thumbnail of Determination of carbon-carbon connectivities, assignment of quaternary carbons, and extraction of carbon-carbon coupling constants by carbon-relayed hydrogen-carbon spectroscopy

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Research paper thumbnail of Cyclic heptapeptides axinastatin 2, 3, and 4: conformational analysis and evaluation of the biological potential

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Research paper thumbnail of Konformationsanalyse von Aminos�ure-Seitenketten in Peptiden durch quantitative Auswertung von Cross-Peaks in COLOC-Spektren

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Automated backbone assignment of labeled proteins using the threshold accepting algorithm

Journal of biomolecular NMR, 1998

The sequential assignment of backbone resonances is the first step in the structure determination... more The sequential assignment of backbone resonances is the first step in the structure determination of proteins by heteronuclear NMR. For larger proteins, an assignment strategy based on proton side-chain information is no longer suitable for the use in an automated procedure. Our program PASTA (Protein ASsignment by Threshold Accepting) is therefore designed to partially or fully automate the sequential assignment of proteins, based on the analysis of NMR backbone resonances plus C beta information. In order to overcome the problems caused by peak overlap and missing signals in an automated assignment process, PASTA uses threshold accepting, a combinatorial optimization strategy, which is superior to simulated annealing due to generally faster convergence and better solutions. The reliability of this algorithm is shown by reproducing the complete sequential backbone assignment of several proteins from published NMR data. The robustness of the algorithm against misassigned signals, no...

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Research paper thumbnail of Hsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules

Nature communications, 2015

The cochaperone Sti1/Hop physically links Hsp70 and Hsp90. The protein exhibits one binding site ... more The cochaperone Sti1/Hop physically links Hsp70 and Hsp90. The protein exhibits one binding site for Hsp90 (TPR2A) and two binding sites for Hsp70 (TPR1 and TPR2B). How these sites are used remained enigmatic. Here we show that Sti1 is a dynamic, elongated protein that consists of a flexible N-terminal module, a long linker and a rigid C-terminal module. Binding of Hsp90 and Hsp70 regulates the Sti1 conformation with Hsp90 binding determining with which site Hsp70 interacts. Without Hsp90, Sti1 is more compact and TPR2B is the high-affinity interaction site for Hsp70. In the presence of Hsp90, Hsp70 shifts its preference. The linker connecting the two modules is crucial for the interaction with Hsp70 and for client activation in vivo. Our results suggest that the interaction of Hsp70 with Sti1 is tightly regulated by Hsp90 to assure transfer of Hsp70 between the modules, as a prerequisite for the efficient client handover.

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Research paper thumbnail of Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging

Theranostics, 2015

Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular traffi... more Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [(68)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [(68)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [(68)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/C...

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Research paper thumbnail of Spectroscopically well-characterized RGD optical probe as a prerequisite for lifetime-gated tumor imaging

Molecular imaging, 2011

Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive im... more Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive imaging of tumors overexpressing ανβ3 integrins. An important prerequisite for optimum detection sensitivity in vivo is strongly absorbing and highly emissive probes with a known fluorescence lifetime. The RGD-Cy5.5 optical probe was derived by coupling Cy5.5 to a cyclic arginine-glycine-aspartic acid-d-phenylalanine-lysine (RGDfK) peptide via an aminohexanoic acid spacer. Spectroscopic properties of the probe were studied in different matrices in comparison to Cy5.5. For in vivo imaging, human glioblastoma cells were subcutaneously implanted into nude mice, and in vivo fluorescence intensity and lifetime were measured. The fluorescence quantum yield and lifetime of Cy5.5 were found to be barely affected on RGD conjugation but dramatically changed in the presence of proteins. By time domain fluorescence imaging, we demonstrated specific binding of RGD-Cy5.5 to glioblastoma xenografts in nu...

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Research paper thumbnail of A Spin System Labeled and Highly Resolved ed-H(CCO)NH-TOCSY Experiment for the Facilitated Assignment of Proton Side Chains in Partially Deuterated Samples

Journal of biomolecular NMR, 1998

The introduction of deuterated and partially deuterated protein samples has greatly facilitated t... more The introduction of deuterated and partially deuterated protein samples has greatly facilitated the 13C assignment of larger proteins. Here we present a new version of the HC(CO)NH-TOCSY experiment, the ed-H(CCO)NH-TOCSY experiment for partially deuterated samples, introducing a multi-quantum proton evolution period. This approach removes the main relaxation source (the dipolar coupling to the directly bound 13C spin) and leads to a significant reduction of the proton and carbon relaxation rates. Thus, the indirect proton dimension can be acquired with high resolution, combined with a phase labeling of the proton resonances according to the C-C spin system topology. This editing scheme, independent of the CHn multiplicity, allows to distinguish between proton side-chain positions occurring within a narrow chemical shift range. Therefore this new experiment facilitates the assignment of the proton chemical shifts of partially deuterated samples even of high molecular weights, as demo...

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Research paper thumbnail of Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2001

The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. ... more The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the alpha(v)beta3 integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed alpha(v)beta3-selective tumor uptake. However, these first-generation compounds predominantly revealed hepatobiliary excretion with high radioactivity found in the liver. In this report, the synthesis and biological evaluation of the first glycosylated RGD-containing peptide (RGD-peptide) for the noninvasive imaging of alpha(v)beta3 expression are described. Peptides were assembled on a solid support using fluorenylmethoxycarbonyl-coupling protocols. The precursor cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP1 was synthesized by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-beta-D-glycero-D-gulo-heptonic acid (SAA(Bn3)) with cyclo(-Arg(Mtr)-Gly-Asp(OtBu)-D-Tyr(tB...

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Research paper thumbnail of Calculating three-dimensional molecular structure from atom-atom distance information: cyclosporin A

International journal of peptide and protein research, 1989

In recent years methods for deriving spatial molecular structure from atom-atom distance informat... more In recent years methods for deriving spatial molecular structure from atom-atom distance information have gained in importance due to the emergence of two-dimensional nuclear magnetic resonance (n.m.r) techniques, which make it possible to obtain such distance information for polypeptides, small proteins, sugars, and DNA fragments in solution. Distance geometry (DG) and restrained molecular dynamics (MD) refinement are applied to a cyclic polypeptide, the immunosuppressive drug cyclosporin A, and the results are compared. Two different procedures, DG followed by restrained MD, and straightforward restrained MD starting from the X-ray structure, both lead to a unique conformation that satisfies the 58 experimentally determined distance constraints. The results nicely show the relative merits of DG and restrained MD techniques for determining spatial molecular structure from distance information.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Improvement of drug-like properties of peptides: the somatostatin paradigm

Expert Opinion on Drug Discovery, 2010

Peptides are promising candidates as therapeutic agents due to their wide involvement in physiolo... more Peptides are promising candidates as therapeutic agents due to their wide involvement in physiological processes. However, their often non-selective activity and their poor drug-like properties, mainly their inherent low stability to enzymatic degradation and poor oral bioavailability, limit their clinical potential. Somatostatin is a peptide hormone involved in many different biological functions. The role of its five different receptor subtypes and their interplay in medicinal processes is only partially understood. In addition, it suffers from poor drug-like properties. We review several promising chemical modifications, including head-to-tail and backbone cyclization as well as N-methylation, which were applied throughout the years in the development of various somatostatin analogs. These modifications led to enhanced metabolic stability and intestinal permeability. In addition, several analogs exhibited specific receptor subtype activation. The results presented in this review suggest a potential use of these chemical modifications in order to achieve required characteristics for a bioactive peptide, mainly for clinical usage.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Mimicking bone extracellular matrix: Integrin-binding peptidomimetics enhance osteoblast-like cells adhesion, proliferation, and differentiation on titanium

Colloids and Surfaces B: Biointerfaces, 2015

Interaction between the surface of implants and biological tissues is a key aspect of biomaterial... more Interaction between the surface of implants and biological tissues is a key aspect of biomaterials research. Apart from fulfilling the non-toxicity and structural requirements, synthetic materials are asked to direct cell response, offering engineered cues that provide specific instructions to cells. This work explores the functionalization of titanium with integrin-binding peptidomimetics as a novel and powerful strategy to improve the adhesion, proliferation and differentiation of osteoblast-like cells to implant materials. Such biomimetic strategy aims at targeting integrins αvβ3 and α5β1, which are highly expressed on osteoblasts and are essential for many fundamental functions in bone tissue development. The successful grafting of the bioactive molecules on titanium is proven by contact angle measurements, X-ray photoelectron spectroscopy and fluorescent labeling. Early attachment and spreading of cells are statistically enhanced by both peptidomimetics compared to unmodified titanium, reaching values of cell adhesion comparable to those obtained with full-length extracellular matrix proteins. Moreover, an increase in alkaline phosphatase activity, and statistically higher cell proliferation and mineralization are observed on surfaces coated with the peptidomimetics. This study shows an unprecedented biological activity for low-molecular-weight ligands on titanium, and gives striking evidence of the potential of these molecules to foster bone regeneration on implant materials.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Human Integrin αvβ5:  Homology Modeling and Ligand Binding

Journal of Medicinal Chemistry, 2004

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Research paper thumbnail of New perspective in peptide chemistry by N-alkylation

Advances in experimental medicine and biology, 2009

Introduction Oral bioavailability is a major concern in the development of peptide based drugs. P... more Introduction Oral bioavailability is a major concern in the development of peptide based drugs. Peptides usually possess high selectivity and potency but the major drawback in their development as a drug is the extremely low oral availability. Insufficient bioavailability of ...

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Research paper thumbnail of A new strategy for the synthesis of cyclopeptides containing diaminoglutaric acid

A new synthesis of orthogonally protected diaminoglutaric acid containing peptides using the Ugi ... more A new synthesis of orthogonally protected diaminoglutaric acid containing peptides using the Ugi four component condensation is presented. To demonstrate that this method is useful to replace cystine by diaminoglutaric acid in biologically interesting peptides, we built up two cyclic somatostatin analogues deriving from Sandostatin and from TT-232. A photolytically cleavable amine derivative of the nitroveratryl type is used for the Ugi four component condensation. Because of a racemic build up of the new stereocentre of the diaminoglutaric acid, and racemization of the isonitrile component, four diastereomeric peptides resulted that were separated by HPLC. The stereochemistry of the cyclopeptides could be easily and unambiguously assigned by chiral gas chromatography and a reference sample of enantiomerically pure (2S,4S)-diaminoglutaric acid.

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Research paper thumbnail of NOESY‐TOCSY, an Advantageous 2D NMR Technique for the Analysis of Peptide Sequences

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Prevention of phalloidin-induced lesions on isolated rat hepatocytes by novel synthetic analogues of somatostatin

Exposure of freshly isolated hepatocytes to phalloidin produced blebs on their surfaces: this phe... more Exposure of freshly isolated hepatocytes to phalloidin produced blebs on their surfaces: this phenomenon was time- and dose-dependent and irreversible. When hepatocytes were pretreated with somatostatin or with some of its synthetic analogues, formation of blebs was dramatically reduced. This cytoprotective effect was dose-dependent: the dose-response profiles enabled the determination of the CD50 values, i.e., the concentrations of analogues that yielded 50% cytoprotection. The analogues with sequences of amino acids in the retro form, compared to those in somatostatin-14, exhibited higher cytoprotection; the retro hexapeptide, cyclo(-Phe-Thr-Lys-D-Trp-Phe-D-Pro-), was 27 times more active than somatostatin-14. Specificity of cytoprotection was examined by pretreating hepatocytes with biologically active peptide hormones prior to exposure to phalloidin. On a molar basis, prolactin and thyroid-stimulating hormone possessed activity comparable to that of somatostatin-14, whereas glucagon was twice as active. Insulin, vitamin A and propranolol exercised less than 10% protection. The synthetic analogues of somatostatin are potent protective agents against cell lesions induced by phalloidin. Formation of blebs on hepatocytes by toxins and their prevention by agents of interest may serve as a suitable morphological assay for screening of cytotoxicity and cytoprotection.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Selection of methyl resonances in proton-detected heteronuclear shift correlation, the HQQC experiment

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Increased resolution in proton detected heteronuclear NMR experiments by folding in the hetero‐dimension

ABSTRACT

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Research paper thumbnail of NMR spectroscopic studies on kinetics and thermodynamics of reversible dissociation reactions. 6. Ionization of tropylium azide in liquid sulfur dioxide and selective migration of the azide ligand in less polar solvents

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Determination of carbon-carbon connectivities, assignment of quaternary carbons, and extraction of carbon-carbon coupling constants by carbon-relayed hydrogen-carbon spectroscopy

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Cyclic heptapeptides axinastatin 2, 3, and 4: conformational analysis and evaluation of the biological potential

Bookmarks Related papers MentionsView impact