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Monobodies as possible next-generation protein therapeutics - a perspective.

ABSTRACT: Over the past two decades, hundreds of new somatic mutations have been identified in tumours, and a few dozen novel cancer therapeutics that selectively target these mutated oncoproteins have entered clinical practice. This development has resulted in clinical breakthroughs for a few tumour types, but more commonly patients' overall survival has not improved because of the development of drug resistance. Furthermore, only a very limited number of oncoproteins, largely protein kinases, are successfully targeted, whereas most non-kinase oncoproteins inside cancer cells remain untargeted. Engineered small protein inhibitors offer great promise in targeting a larger variety of oncoproteins with better efficacy and higher selectivity. In this article, I focus on a promising class of synthetic binding proteins, termed monobodies, that we have shown to inhibit previously untargetable protein-protein interactions in different oncoproteins. I will discuss the great promise alongside the technical challenges inherent in converting monobodies from potent pre-clinical target validation tools to next-generation protein-based therapeutics.

SUBMITTER: Hantschel O

PROVIDER: S-EPMC7316567 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Monobodies as possible next-generation protein therapeutics - a perspective.

Hantschel Oliver O

Swiss medical weekly 20171120

Over the past two decades, hundreds of new somatic mutations have been identified in tumours, and a few dozen novel cancer therapeutics that selectively target these mutated oncoproteins have entered clinical practice. This development has resulted in clinical breakthroughs for a few tumour types, but more commonly patients' overall survival has not improved because of the development of drug resistance. Furthermore, only a very limited number of oncoproteins, largely protein kinases, are succes ...[more]

PMID: 29185244

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Project description:In this perspective, we describe our efforts to innovate the current isotope-aided NMR methodology to investigate biologically important large proteins and protein complexes, for which only limited structural information could be obtained by conventional NMR approaches. At the present time, it is widely believed that only backbone amide and methyl signals are amenable for investigating such difficult targets. Therefore, our primary mission is to disseminate our novel knowledge within the biological NMR community; specifically, that any type of NMR signals other than methyl and amide groups can be obtained, even for quite large proteins, by optimizing the transverse relaxation properties by isotope labeling methods. The idea of "TROSY by isotope labeling" has been cultivated through our endeavors aiming to improve the original stereo-array isotope labeling (SAIL) method (Kainosho et al., Nature 440:52-57, 2006). The SAIL TROSY methods subsequently culminated in the successful observations of individual NMR signals for the side-chain aliphatic and aromatic 13CH groups in large proteins, as exemplified by the 82 kDa single domain protein, malate synthase G. Meanwhile, the expected role of NMR spectroscopy in the emerging integrative structural biology has been rapidly shifting, from structure determination to the acquisition of biologically relevant structural dynamics, which are poorly accessible by X-ray crystallography or cryo-electron microscopy. Therefore, the newly accessible NMR probes, in addition to the methyl and amide signals, will open up a new horizon for investigating difficult protein targets, such as membrane proteins and supramolecular complexes, by NMR spectroscopy. We briefly introduce our latest results, showing that the protons attached to 12C-atoms give profoundly narrow 1H-NMR signals even for large proteins, by isolating them from the other protons using the selective deuteration. The direct 1H observation methods exhibit the highest sensitivities, as compared to heteronuclear multidimensional spectroscopy, in which the 1H-signals are acquired via the spin-coupled 13C- and/or 15N-nuclei. Although the selective deuteration method was launched a half century ago, as the first milestone in the following prosperous history of isotope-aided NMR methods, our results strongly imply that the low-dimensional 1H-direct observation NMR methods should be revitalized in the coming era, featuring ultrahigh-field spectrometers beyond 1 GHz.

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Monobodies as possible next-generation protein therapeutics - a perspective.

Publications

Monobodies as possible next-generation protein therapeutics - a perspective.

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