Cell-based peptide screening to access the undruggable target space

Hennemann, Hanjo; Wirths, Sabine; Carl, C.

doi:10.1016/j.ejmech.2014.10.038

Cited by 16 publications

(8 citation statements)

References 58 publications

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“…Target-based drug discovery has gained prominence with growing understanding of cellular networks and molecular targets from genome sequencing[3, 10]. Several methods, including ELISA-based screens, split luciferase, and yeast two-hybrid assays, are widely used to screen compounds against a desired protein of interest both in vitro and in vivo [11]. These approaches do not require an intimate knowledge of the molecular details of targeted protein interfaces.…”

Section: Target-based Screensmentioning

confidence: 99%

Systematic Targeting of Protein–Protein Interactions

Modell

Blosser

Arora

2016

Trends in Pharmacological Sciences

159

143

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Over the past decade, protein-protein interactions have gone from being neglected as “undruggable” to being considered attractive targets for the development of therapeutics. Recent advances in computational analysis, fragment-based screening and molecular design have revealed promising strategies to address the basic molecular recognition challenge: how to target large protein surfaces with specificity. Several systematic and complementary workflows have been developed to yield successful inhibitors of protein-protein interactions. Herein we review the major contemporary approaches utilized for the discovery of inhibitors and focus on a structure-based workflow, from the selection of a biological target through design.

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Section: Target-based Screensmentioning

confidence: 99%

Systematic Targeting of Protein–Protein Interactions

Modell

Blosser

Arora

2016

Trends in Pharmacological Sciences

159

143

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“…Even if these molecules fall outside the Lipinski “rules of 5” and therefore represent a challenge regarding the optimization of their ADME properties, their size might be inadequate to tackle difficult targets and modes of action such as protein–protein interactions. Indeed, hexamers might have an appropriate molecular size if the target contains a deep pocket for ligand binding; however, if the activity‐relevant interface of the target consists of a flat region, their size might be a true limiting factor for high affinity ,. Therefore, we decided to investigate cyclic decapeptides, which we believed would be better able to interfere with such flat and large interfaces.…”

Section: Introductionmentioning

confidence: 99%

Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure

et al. 2016

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Permeability and oral bioavailability of macrocyclic peptides still represent difficult challenges in drug discovery. Despite the recognized potential of macrocyclic peptides as therapeutics, their use is still restricted to extracellular targets and intravenous administration. Indeed, macrocyclic peptides generally suffer from limited proteolytic stability, high clearance, and poor membrane permeability, and this leads to the absence of systemic exposure after oral administration. To overcome these limitations, we started to investigate the development of a general cyclic decapeptide scaffold that possesses ideal features for cell permeability and oral exposure. On the basis of a rigid hairpin structure, the scaffold design aimed to decrease the overall polarity of the compound, thereby limiting the energetic cost of NH desolvation and the entropy penalty during cell penetration. The results of this study also demonstrate the importance of rigidity for the β-turn design regarding clearance. To stabilize the scaffold in the desired β-hairpin conformation, the introduction of d-proline at the i+1 turn position proved to be beneficial for both permeability and clearance. As a result, cyclopeptide decamers with unprecedented high values for oral bioavailability and exposure are reported herein. NMR spectroscopy conformation and dynamic analysis confirmed, for selected examples, the rigidity of the scaffold and the presence of transannular hydrogen bonds in polar and apolar environments. Furthermore, we showed, for one compound, that its transition from a polar environment to an apolar one was accompanied by an increased molecular motion, revealing an entropy contribution to membrane permeation.

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“…Thus, this changeover in bacterial resistance has urged the scientific community to seek an active and efficient alternative. Peptides are widely accepted as a best potent alternative for classical antibiotics to treat bacterial resistance as they are safe, tolerable, efficient, highly selective, and smaller in size . Among the peptides the cyclotides, a naturally occurring peptide found in the Rubiaceae, Violaceae, Cucurbitaceae, and Apocynaceae plant families has a characteristic cyclic cysteine knot motif .…”

Section: Introductionmentioning

confidence: 99%

The structural and functional reliability of Circulins of Chassalia parvifolia for peptide therapeutic scaffolding

Balaraman

Rajasekaran

2018

J of Cellular Biochemistry

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Computational methods have refined the mode of peptide drug designing to a new plateau recently. Circulin, a 30 residue natural plant polypeptide acts as a plant defensive peptide. Additional to its antimicrobial activity it also possesses an inhibitory cytopathic effect on the replication of human immunodeficiency virus (HIV). Stable Circulin can be a functionally able template for scaffolding peptide based drugs. Hence, structural stability of Chassalia parvifolia, Circulin A (1BH4), and Circulin B (2ERI) was computationally investigated. From this analysis, the stability favored toward Circulin B which was supported by various parameters such as intra-molecular interactions (61), secondary structure, hydrophobicity (67.34%), root mean square deviation (2.64Å), root mean square fluctuation (0.08Å), radius of gyration (8.96Å), ovality (3.49), angular deviation (73.6%), surface area (both polar and non-polar), hydrogen bond distribution (11.94), and disulphide bond distances. Further, the functional activity calculated in terms of membrane associated free energy (-4.10 kcal/mol) also favored Circulin B. Hence, Circulin B could be proposed as the best template for scaffolding antimicrobial as well as antiviral (HIV) peptide based drug design. The obtained computational data can aid experimental biologists to successfully produce stable therapeutic peptides from natural resources reducing erroneous wastage of monetary sources and time.

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Cell-based peptide screening to access the undruggable target space

Cited by 16 publications

References 58 publications

Systematic Targeting of Protein–Protein Interactions

Systematic Targeting of Protein–Protein Interactions

Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure

The structural and functional reliability of Circulins of Chassalia parvifolia for peptide therapeutic scaffolding

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