Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri, Walter; Cantelmi, Paolo; Corbisiero, Dario; Fantoni, Tommaso; Ferrazzano, Lucia; Martelli, Giulia; Mattellone, Alexia; Tolomelli, Alessandra

doi:10.3389/fmolb.2021.697586

Cited by 76 publications

(65 citation statements)

References 124 publications

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“…It is in marked contrast with the total number of clinically significant PPIs whose interface can be modulated by drugs. In the analytical review by Cabri and co-authors [ 142 ], there were found 58 therapeutic peptides that occurred in CT’s reports. Of these, 13, 26 and 15 are in phase I, II and III, respectively, and 4 peptides are close to FDA approval (BBT-401, Foxy-5, Nangibotide and Reltecimod) [ 142 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the analytical review by Cabri and co-authors [ 142 ], there were found 58 therapeutic peptides that occurred in CT’s reports. Of these, 13, 26 and 15 are in phase I, II and III, respectively, and 4 peptides are close to FDA approval (BBT-401, Foxy-5, Nangibotide and Reltecimod) [ 142 ]. The first trial with 71 enrolled participants studied ALRN-6924 formulation containing the peptide inhibitor of MDM2/p53 for tumors with the wild-type TP53 gene.…”

Section: Discussionmentioning

confidence: 99%

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Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

2022

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The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

2022

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“…The increasing number of peptides entering clinical trials year by year indicates that there is a growing interest from the side of pharmaceutical companies in the use of this class of molecules as drugs [ 14 , 15 , 16 ]. To date, the number of therapeutic peptides approved is 70 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Downstream Processing of Therapeutic Peptides by Means of Preparative Liquid Chromatography

et al. 2021

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The market of biomolecules with therapeutic scopes, including peptides, is continuously expanding. The interest towards this class of pharmaceuticals is stimulated by the broad range of bioactivities that peptides can trigger in the human body. The main production methods to obtain peptides are enzymatic hydrolysis, microbial fermentation, recombinant approach and, especially, chemical synthesis. None of these methods, however, produce exclusively the target product. Other species represent impurities that, for safety and pharmaceutical quality reasons, must be removed. The remarkable production volumes of peptide mixtures have generated a strong interest towards the purification procedures, particularly due to their relevant impact on the manufacturing costs. The purification method of choice is mainly preparative liquid chromatography, because of its flexibility, which allows one to choose case-by-case the experimental conditions that most suitably fit that particular purification problem. Different modes of chromatography that can cover almost every separation case are reviewed in this article. Additionally, an outlook to a very recent continuous chromatographic process (namely Multicolumn Countercurrent Solvent Gradient Purification, MCSGP) and future perspectives regarding purification strategies will be considered at the end of this review.

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“…The first peptide used in treating disease was the hormone insulin in the 1920s [2,5,6]. Since then, peptide-based drugs have played a crucial role in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Expanding the Use of Dynamic Electrostatic Repulsion Reversed-Phase Chromatography: An Effective Elution Mode for Peptides Control and Analysis

Mazzoccanti

Manetto

Bassan³

et al. 2021

Molecules

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Bioactive peptides are increasingly used in clinical practice. Reversed-phase chromatography using formic or trifluoroacetic acid in the mobile phase is the most widely used technique for their analytical control. However, sometimes it does not prove sufficient to solve challenging chromatographic problems. In the search for alternative elution modes, the dynamic electrostatic repulsion reversed-phase was evaluated to separate eight probe peptides characterised by different molecular weights and isoelectric points. This technique, which involves TBAHSO4 in the mobile phase, provided the lowest asymmetry and peak width at half height values and the highest in peak capacity (about 200 for a gradient of 30 min) and resolution concerning the classic reversed-phase. All analyses were performed using cutting-edge columns developed for peptide separation, and the comparison of the chromatograms obtained shows how the dynamic electrostatic repulsion reversed-phase is an attractive alternative to the classic reversed-phase.

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Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cited by 76 publications

References 124 publications

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

Downstream Processing of Therapeutic Peptides by Means of Preparative Liquid Chromatography

Expanding the Use of Dynamic Electrostatic Repulsion Reversed-Phase Chromatography: An Effective Elution Mode for Peptides Control and Analysis

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