Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides

In cancer, proliferation of malignant cells is driven by overactivation of growth-signalling mechanisms, such as the epidermal growth factor receptor (EGFR) pathway. Despite its therapeutic relevance, the EGF-EGFR interaction has remained elusive to inhibition by synthetic molecules, mostly as a result of its large size and lack of binding pockets and cavities. Designed peptides, featuring cyclic motifs and other structural constraints, have the potential to modulate such challenging protein-protein interactions (PPIs). Herein, we present the structure-based design of a series of bicyclic constrained peptides that mimic an interface domain of EGFR and inhibit the EGF-EGFR interaction by targeting the smaller partner (i.e., EGF). This design process was guided by the integrated use of in silico methods and biophysical techniques, such as NMR spectroscopy and surface acoustic wave. The best analogues were able to reduce selectively the viability of EGFR+ human cancer cells. In addition to their efficacy, these bicyclic peptides are endowed with exceptional stability and metabolic resistance-two features that make them suitable candidates for in vivo applications

Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics

Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration of action, poor protease selectivity, and low blood-brain barrier (BBB) permeability, which altogether limit their potential as drugs. Here, we describe the structure-based design of the first irreversible, selective, and brain-permeable POP inhibitors. At low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, both in vitro and in human cells. More importantly, they are >1,000-fold selective against two family-related proteases (DPPIV and FAP) and display high BBB permeability, as shown in both lipid membranes and MDCK cells

IDP-410: a novel therapeutic peptide that alters N-MYC stability and reduces angiogenesis and tumor progression in glioblastomas

13 p.-7 fig.Glioblastomas (GBMs) are the most frequent and highly aggressive brain tumors, being resistant to all cytotoxic and molecularly targeted agents tested so far. There is, therefore, an urgent need to find novel therapeutic approaches and/or alternative targets to bring treatment options to patients. Here, we first show that GBMs express high levels of N-MYC protein, a transcription factor involved in normal brain development. A novel stapled peptide designed to specifically target N-MYC protein monomer, IDP-410, is able to impair the formation of N-MYC/MAX complex and reduce the stability of N-MYC itself. As a result, the viability of GBM cells is compromised. Moreover, the efficacy is found dependent on the levels of expression of N-MYC. Finally, we demonstrate that IDP-410 reduces GBM growth in vivo when administered systemically, both in subcutaneous and intracranial xenografts, reducing the vascularization of the tumors, highlighting a potential relationship between the function of N-MYC and the expression of mesenchymal/angiogenic genes. Overall, our results strengthen the view of N-MYC as a therapeutic target in GBM and strongly suggest that IDP-410 could be further developed to become a first-in-class inhibitor of N-MYC protein, affecting not only tumor cell proliferation and survival, but also the interplay between GBM cells and their microenvironment.This work was supported by Ministerio de Economía y Competitividad: (Acción Estratégica en Salud) and FEDER funds: PI16/01550 to JMS, by “Asociación Española contra el Cancer” grants: INVES192GARG to RG, GCTRA16015SEDA to JMS, and IDEAS20095SÁNC to PSG, and by Ministerio de Ciencia, Innovación y Universidades and FEDER funds: RTI2018-093596 to PSG. MGA was supported by the Young Employment Initiative (Comunidad de Madrid).Peer reviewe

What Design Research Does ... : 62 Cards Highlighting the Power and Impact of UK-based Design Research in Addressing a Range of Complex Social, Economic, Cultural and Environmental Issues

Design research makes a significant contribution to the UK economy and society as a whole. Ever since the establishment of the Government Schools of Design in the nineteenth century, the UK has been widely acknowledged as an international leader in design research. Following this lead, the What Design Research Does… cards highlight the wide range of social, economic, cultural and environmental impacts that design research, funded and based in the UK, makes all over the world. The 62 cards illustrate unambiguously the positive changes that contemporary UK-based design researchers are making in many complex issues. Each What Design Research Does… card lists the challenges and issues faced by the design researchers, who they collaborated with, the research methods and approaches taken, the outcomes of the design research, what the main results and findings have been, and what impact the design research has had. In short, the What Design Research Does… cards clearly articulate the breadth of social, economic, cultural and environmental impacts that UK-based design researchers are achieving today

Super-secondary structure peptidomimetics: design and synthesis of an a–a hairpin analogue

The ?–? helix motif presents key recognition domains in protein–protein and protein–oligonucleotide binding, and is one of the most common super-secondary structures. Herein, we describe the design, synthesis and structural characterisation of an ?–? hairpin analogue based on a tetra-coordinated Pd(II) bis-(iminoisoquinoline) complex as a template for the display of two ?-helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the side chains of the i and i+4 residues of two helices

Gaseous- versus solution-phase recognition of some aromatic amino esters by 2,8,14,20-tetrakis(L-valinamido)[4]resorcinarene

The effects of the physical environment on the molecular recognition of some aromatic amino esters (A = 3-(3,4)dihydroxyphenyl)alanine methyl ester (DOPAOMe), 3-(3,4)dihydroxyphenyl)alanine ethyl ester (DOPAOEt) and tryptophan ethyl ester (trpOEt)) by the flattened-cone 2,8,14,20- tetrakis(L-valinamido)[4]resorcinarene (1L) have been investigated in both the gas-phase by ESI-MS spectrometry and in CDCl3 solutions by 1H and 13C NMR spectroscopy. It is found that the non-covalent [1L·H·DOPAOMe]+ and [1L·H·DOPAOEt]+ complexes are stable in the gas-phase. The last one is stable in CDCl3 solutions as well, while [1L·H·trpOEt]+ is not. The formation of the stable [1L·H·DOPAOEt]+ complex in CDCl3 is not affected by the presence of traces of additives, like D2O, DCl or ethyl acetate, or by absorption on silica. APT-13C NMR analysis of [1L·H·DOPAOEt]+ suggests that the amino ester is mainly located inside the resorcinarene cavity, in conformity with the most stable structure arising from MC/MD simulations

The contribution of oxazolidinone frame to the biological activity of pharmaceutical drugs and natural products

The development of resistance by the antibiotics in the Gram-positive pathogenic bacteria over the last twenty years and continuing today has created a need for new antibiotic classes, which may be unaffected by existing bacterial resistance. The oxazolidin-2-ones represent not only a new class with a novel mechanism of action, but also satisfy the requirement for overcoming the resistance mechanisms. Both linezolid and eperozolid, the first chemical candidates, arose from the piperazine subclass, with the first one being chosen further development because of its enhanced pharmacokinetic properties. The main attractive traits of the oxazolidinone series has encouraged further work in the area, and the patent literature reveals that extensive chemical investigation is currently being made. The unexpected early resistance development emphasizes the need for further exploration of features of the oxazolidinone to eliminate these deficiencies. Recently, several changes, involving the C5 side chain as well the N-phenyl heterocyclic ring, give promise for such improvement. Oxazolidinone antibacterial agents comprise also ketolides, derivatives of macrolides, such as erythromycin A, with a newly formed carbamate cycle, with a largely unexplored potential. The oxazolidinone nucleus does not appear only in the structures of antimicrobial drugs, but a number of biological activities are connected with frameworks including the oxazolidinone ring. A partial list of these activities comprises enzyme inhibitors, agonists and antagonists, with a particular citation for a new generation of selective monoamino oxidase inhibitors (befloxatone). The oxazolidinone moiety was found in the structure of few biologically active natural products, such as (-)-cytoxazone and streptazolin. Moreover, in some cases the oxazolidinone ring has been chosen for the preparation of isosteric aza analogues of natural compounds (podophyllotoxin, pilocarpine) that can be more easily synthesised and more hardly inactivated. Finally, the participation of oxazolidinone chiral auxiliaries to several syntheses of natural products must be acknowledged

Oxazolidin-2-one ring, a popular framework in synthetic organic chemistry: Part 1. The construction of the oxazolidin-2-one ring

The 1,3-oxazolidin-2-one nucleus is a popular heterocycle framework in synthetic organic chemistry, as well as in medicinal chemistry. This paper deals with the huge number of synthetic approaches addressed to the construction of this five-member ring, with a particular care for the mechanistic and stereochemical outcome

Targeted Nanoswitchable Inhibitors of Protein–Protein Interactions Involved in Apoptosis

Progress in drug delivery is hampered by a lack of efficient strategies to target drugs with high specificity and precise spatiotemporal regulation. The remote control of nanoparticles and drugs with light allows regulation of their action site and dosage. Peptide-based drugs are highly specific, non-immunogenic, and can be designed to cross the plasma membrane. In order to combine target specificity and remote control of drug action, here we describe a versatile strategy based on a generalized template to design nanoswitchable peptides that modulate protein-protein interactions upon light activation. This approach is demonstrated to promote photomodulation of two important targets involved in apoptosis (the interactions Bcl-xL-Bak and MDM2-p53), but can be also applied to a large pool of therapeutically relevant protein-protein interactions mediated by α-helical motifs. The template can be adjusted using readily available information about hot spots (residues contributing most to the binding energy) at the protein-protein interface of interest