Nathalie Grob

Last Name

Grob

First Name

Nathalie

ORCID

0000-0003-1031-5105

Organisational unit

09833 - Grob, Nathalie M. / Grob, Nathalie M.

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Publications 1 - 10 of 11

Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis
Rössler, Simon; Grob, Nathalie; Buchwald, Stephen L.; et al. (2023)
Science
During the early stages of drug discovery, chemists often expose target proteins to vast libraries of small molecules in the hope of finding one that binds tightly. Tagging the molecules with small fragments of DNA has proven a convenient means of interpreting the screen at concentrations where it would otherwise be hard to determine which of them were bound. However, nucleotide structure constrains the chemistry applicable to making the drug candidates. Rössler et al. now showcase an alternative method in which the tags consist of peptides in place of oligonucleotides, expanding the scope of compatible chemistry (see the Perspective by Haap). —JSY
Methoxinine – an alternative stable amino acid substitute for oxidation-sensitive methionine in radiolabelled peptide conjugates
Grob, Nathalie; Behe, Martin; Von Guggenberg, Elisabeth; et al. (2017)
Journal of Peptide Science
Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N
Grob, Nathalie; Schibli, Roger; Behe, Martin; et al. (2021)
Cancers
The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with 177Lu3+, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu10-Ala11 and/or Tyr12-Gly13 showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms.
Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity
Vretto, Eirinaios I.; Valverde, Ibai E.; Mascarin, Alba; et al. (2020)
Chemistry - A European Journal
Mutating the side-chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half-life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT2R/AT1R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross-peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Triazole-Based Radiopeptidomimetics: Analogs of Minigastrin with Improved Tumor-Targeting Characteristics
Grob, Nathalie (2019)
Beyond the Canonical 20: Peptide Discovery with Non-Canonical Amino Acids
Grob, Nathalie (2025)
Chimia
Amino acids are central to biology as signaling molecules and as the building blocks of peptides and proteins, which represent an expanding class of drugs with vast therapeutic potential. The precise modulation of individual residues in therapeutic peptides and proteins is crucial to enhance their pharmacological properties. Expanding beyond the twenty proteinogenic amino acids to include non-canonical amino acids (ncAAs) offers powerful strategies to optimize the stability, selectivity, and potency of peptides. Including ncAAs in the early discovery phase can significantly accelerate lead development and clinical translation. This review examines how diverse platforms integrate ncAAs in early discovery and compares the capabilities and limitations of these discovery technologies. Finally, key challenges are outlined that must be addressed to drive future innovations and explore new therapeutic avenues. Together, these approaches mark a shift towards peptide drug discovery where non-canonical chemistry is not an exception but a necessity.
1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs
Grob, Nathalie; Schibli, Roger; Behe, Martin; et al. (2021)
ACS Medicinal Chemistry Letters
1,5-Disubstituted 1,2,3-triazoles (1,5-Tz) are considered bioisosteres of cis-amide bonds. However, their use for enhancing the pharmacological properties of peptides or proteins is not yet well established. Aiming to illustrate their utility, we chose the peptide conjugate [Nle15]MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) as a model compound since it is known that the cholecystokinin-2 receptor (CCK2R) is able to accommodate turn conformations. Analogs of [Nle15]MG11 incorporating 1,5-Tz in the backbone were synthesized and radiolabeled with lutetium-177, and their pharmacological properties (cell internalization, receptor binding affinity and specificity, plasma stability, and biodistribution) were evaluated and compared with [Nle15]MG11 as well as their previously reported analogs bearing 1,4-disubstituted 1,2,3-triazoles. Our investigations led to the discovery of novel triazole-modified analogs of [Nle15]MG11 with nanomolar CCK2R-binding affinity and 2-fold increased tumor uptake. This study illustrates that substitution of amides by 1,5-disubstituted 1,2,3-triazoles is an effective strategy to enhance the pharmacological properties of biologically active peptides.
Design of Radiolabeled Analogs of Minigastrin by Multiple Amide-to-Triazole Substitutions
Grob, Nathalie; Schmid, Sarah; Schibli, Roger; et al. (2020)
Journal of Medicinal Chemistry
Corrigendum concerning “Methoxinine—An alternative stable amino acid substitute for oxidation‐sensitive methionine in radiolabelled peptide conjugates”
Grob, Nathalie; Behe, Martin; Von Guggenberg, Elisabeth; et al. (2020)
Journal of Peptide Science
Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting
Grob, Nathalie; Häussinger, Daniel; Deupi, Xavier; et al. (2020)
Journal of Medicinal Chemistry

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Nathalie Grob

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