Synthetic Pept-Ins as a Generic Amyloid-Like Aggregation-Based Platform for <i>In Vivo</i> PET Imaging of Intracellular Targets

Siemons, Maxime; Luyten, Kaat; Khodaparast, Laleh; Lecina, Joan; Claes, Filip; Gallardo, Rodrigo; Ramakers, Meine; Schymkowitz, Joost; Bormans, Guy; Rousseau, Frédéric

doi:10.1021/acs.bioconjchem.1c00369

Cited by 4 publications

(3 citation statements)

References 52 publications

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“…APRs normally participate in the folding and stabilization of the native state ( 5 , 49 ). Protein misfolding and aggregation results from the self-association of such APRs into beta-sheet structured amyloid-like assemblies can be induced by synthetic amyloid peptides called Pept-ins another binding mode, which exploits the self-interacting properties of aggregating protein sequences ( 6 – 7 , 8 , 34 , 37 – 54 ).…”

Section: Discussionmentioning

confidence: 99%

Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein

Janssen

Claes²,

Velde³

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Mutant KRAS is a major driver of oncogenesis in a multitude of cancers but remains a challenging target for classical small molecule drugs, motivating the exploration of alternative approaches. Here, we show that aggregation-prone regions (APRs) in the primary sequence of the oncoprotein constitute intrinsic vulnerabilities that can be exploited to misfold KRAS into protein aggregates. Conveniently, this propensity that is present in wild-type KRAS is increased in the common oncogenic mutations at positions 12 and 13. We show that synthetic peptides (Pept-ins™) derived from two distinct KRAS APRs could induce the misfolding and subsequent loss of function of oncogenic KRAS, both of recombinantly produced protein in solution, during cell-free translation and in cancer cells. The Pept-ins exerted antiproliferative activity against a range of mutant KRAS cell lines and abrogated tumor growth in a syngeneic lung adenocarcinoma mouse model driven by mutant KRAS G12V. These findings provide proof-of-concept that the intrinsic misfolding propensity of the KRAS oncoprotein can be exploited to cause its functional inactivation.

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Section: Discussionmentioning

confidence: 99%

Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein

Janssen

Claes²,

Velde³

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Synthetic amyloid peptides, also called peptins, were used as vector probes that could adhere to microbial and mammalian proteins. PET scans utilizing these radiolabeled probes, including [68Ga]Ga-NODAGA-PEG2-P2, that target Escherichia coli, have been found to efficiently identify intracellular targets [ 26 ].…”

Section: Reviewmentioning

confidence: 99%

Radiological and Imaging Evidence in the Diagnosis and Management of Microbial Infections: An Update

Vaishnav,

Gurukiran,

Ighodaro

et al. 2023

Cureus

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Microbial infections are extremely prevalent throughout the world. Bacteria, fungi, parasites, and viruses generally cause them. Most microbial infections spread from humans to humans and from animals to humans. A vast majority of microbial infections are self-limiting. However, some microbial infections result in severe morbidity and mortality. The diagnosis of microbial infections generally depends on the direct demonstration of microbes in human clinical specimens through microscopy followed by culture. Some microbes are uncultivable, and among those that are cultivable, some take a very long time to grow in the laboratory. This causes delays in the diagnosis that may result in poor patient outcomes. Serological and molecular methods like enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), respectively, have been extensively used to diagnose infectious diseases. However, these require costly infrastructure and adequate personnel training. In this context, alternative, more efficient, and rapid detection methods for the diagnosis of microbial infections are warranted. In this review, we comprehensively discuss the role played by radiological investigations in the diagnosis and management of infectious diseases.

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“…There is a lot of evidence for the biological activity of proteins and peptides that exhibit the ability to aggregate [1][2][3][4][5][6][7][8]. There is some relationship between the amyloidogenic and antimicrobial properties of peptide(s), the reasons for which have not been fully known [9].…”

Section: Introductionmentioning

confidence: 99%

Amyloidogenic Peptides: New Class of Antimicrobial Peptides with the Novel Mechanism of Activity

Galzitskaya

Kurpe

Panfilov

et al. 2022

IJMS

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Antibiotic-resistant bacteria are recognized as one of the leading causes of death in the world. We proposed and successfully tested peptides with a new mechanism of antimicrobial action “protein silencing” based on directed co-aggregation. The amyloidogenic antimicrobial peptide (AAMP) interacts with the target protein of model or pathogenic bacteria and forms aggregates, thereby knocking out the protein from its working condition. In this review, we consider antimicrobial effects of the designed peptides on two model organisms, E. coli and T. thermophilus, and two pathogenic organisms, P. aeruginosa and S. aureus. We compare the amino acid composition of proteomes and especially S1 ribosomal proteins. Since this protein is inherent only in bacterial cells, it is a good target for studying the process of co-aggregation. This review presents a bioinformatics analysis of these proteins. We sum up all the peptides predicted as amyloidogenic by several programs and synthesized by us. For the four organisms we studied, we show how amyloidogenicity correlates with antibacterial properties. Let us especially dwell on peptides that have demonstrated themselves as AMPs for two pathogenic organisms that cause dangerous hospital infections, and in which the minimal inhibitory concentration (MIC) turned out to be comparable to the MIC of gentamicin sulfate. All this makes our study encouraging for the further development of AAMP. The hybrid peptides may thus provide a starting point for the antibacterial application of amyloidogenic peptides.

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Synthetic Pept-Ins as a Generic Amyloid-Like Aggregation-Based Platform for In Vivo PET Imaging of Intracellular Targets

Cited by 4 publications

References 52 publications

Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein

Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein

Radiological and Imaging Evidence in the Diagnosis and Management of Microbial Infections: An Update

Amyloidogenic Peptides: New Class of Antimicrobial Peptides with the Novel Mechanism of Activity

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