Chemically Modified Poly(A) Analogs Targeting PABP: Structure Activity Relationship and Translation Inhibitory Properties

Perzanowska, Olga; Śmietański, Mirosław; Jemielity, Jacek; Kowalska, Joanna

doi:10.1002/chem.202201115

Cited by 5 publications

(2 citation statements)

References 54 publications

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“…Interestingly, those differ from the sequences investigated by Perzanowska et al (2022). In particular, the pair of sequences having highest affinity in the study, was not found in our list.…”

Section: Designcontrasting

confidence: 62%

“…To illustrate the capacity of MFEdock to address design, we considered a design study recently published by Perzanowska et al (2022), where an oligonucleotide targeting a poly(A)-binding protein (PDBID: 1CVJ) was designed. Since this study included modified nucleotides, we considered an extended list of nucleotides: two without modification (A,G), and 5 with modifications: adenosine and guanosine with a phosphorothioate (AP , GP ), protonated adenosine (A ψ ), N6-methyladenosine (m 6 A), N6-methyladenosine including phosphorothioate (m 6 AP ), O-methyladenosine (Am) and Omethyladenosine including phosphorothioate (AmP ).…”

Section: Designmentioning

confidence: 99%

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Color Coding for the Fragment-Based Docking, Design and Equilibrium Statistics of Protein-Binding ssRNAs

Yacoub,

González-Alemán,

Leclerc

et al. 2024

Lecture Notes in Computer Science

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We revisit the fragment-based docking and design of single-stranded RNA aptamers (ssR-NAs), consisting of k nucleotides, onto a rigid protein. Fragments, representing either one or multiple pieced nucleotides, are individually docked onto the protein surface using a force field, and some among the resulting n poses are pieced together to form a conformation compatible with the input ssRNA sequence. Relaxing the sequence compatibility constraint, a similar methodology can be used to design ssRNAs that preferentially bind a protein of interest, possibly targeting a pocket. However, a bruteforce enumeration of clash-free conformations quickly becomes prohibitive due to their superexponential (Θ(n k ) worst-case) combinatorial explosion, hindering the potential of fragment-based methods towards docking and design.We adopt the color-coding technique, introduced by Alon, Yuster and Zwick, to optimize over selfavoiding fragment assemblies in time/space linear on n the number of poses, and in time only exponential on k the number of fragments. The dynamic programming algorithm at the core of our method is surprisingly simple, and can be extended to produce suboptimal candidates, or modified to perform Boltzmann sampling of candidates assemblies. Using a rejection principle, and further optimized by a clique decomposition of clashing poses, these algorithms can be leveraged into efficient algorithms optimizing over clash-free complexes. The resulting sampling procedure can further be adapted into statistically-consistent estimators for any computable feature of interest.We showcase some of the capabilities of this new framework by reanalyzing a set of 7 documented ssRNA-protein complexes, demonstrating its practical relevance and versatility.

show abstract

Section: Designcontrasting

confidence: 62%

Section: Designmentioning

confidence: 99%

Color Coding for the Fragment-Based Docking, Design and Equilibrium Statistics of Protein-Binding ssRNAs

Yacoub,

González-Alemán,

Leclerc

et al. 2024

Lecture Notes in Computer Science

View full text Add to dashboard Cite

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Chemically Modified Poly(A) Analogs Targeting PABP: Structure Activity Relationship and Translation Inhibitory Properties

Perzanowska

Śmietański

Jemielity

et al. 2022

Chemistry A European J

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Poly(A)-binding protein (PABP) is an essential element of cellular translational machinery. Recent studies have revealed that poly(A) tail modifications can modulate mRNA stability and translational potential, and that oligoadenylate-derived PABP ligands can act as effective translational inhibitors with potential applications in pain management.Although extensive research has focused on protein-RNA and protein-protein interactions involving PABPs, further studies are required to examine the ligand specificity of PABP. In this study, we developed a microscale thermophoresis-based assay to probe the interactions between PABP and oligoadenylate analogs containing different chemical modifications.Using this method, we evaluated oligoadenylate analogs modified with nucleobase, ribose, and phosphate moieties to identify modification hotspots. In addition, we determined the susceptibility of the modified oligos to CNOT7 to identify those with the potential for increased cellular stability. Consequently, we selected two enzymatically stable oligoadenylate analogs that inhibit translation in rabbit reticulocyte lysates with a higher potency than a previously reported PABP ligand. We believe that the results presented in this study and the implemented methodology can be capitalized upon in the future development of RNA-based biological tools.

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Neoantigen vaccine nanoformulations based on Chemically synthesized minimal mRNA (CmRNA): small molecules, big impact

Imani,

Tagit,

Pichon

2024

npj Vaccines

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Recently, chemically synthesized minimal mRNA (CmRNA) has emerged as a promising alternative to in vitro transcribed mRNA (IVT-mRNA) for cancer therapy and immunotherapy. CmRNA lacking the untranslated regions and polyadenylation exhibits enhanced stability and efficiency. Encapsulation of CmRNA within lipid-polymer hybrid nanoparticles (LPPs) offers an effective approach for personalized neoantigen mRNA vaccines with improved control over tumor growth. LPP-based delivery systems provide superior pharmacokinetics, stability, and lower toxicity compared to viral vectors, naked mRNA, or lipid nanoparticles that are commonly used for mRNA delivery. Precise customization of LPPs in terms of size, surface charge, and composition allows for optimized cellular uptake, target specificity, and immune stimulation. CmRNA-encoded neo-antigens demonstrate high translational efficiency, enabling immune recognition by CD8+ T cells upon processing and presentation. This perspective highlights the potential benefits, challenges, and future directions of CmRNA neoantigen vaccines in cancer therapy compared to Circular RNAs and IVT-mRNA. Further research is needed to optimize vaccine design, delivery, and safety assessment in clinical trials. Nevertheless, personalized LPP-CmRNA vaccines hold great potential for advancing cancer immunotherapy, paving the way for personalized medicine.

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Chemically Modified Poly(A) Analogs Targeting PABP: Structure Activity Relationship and Translation Inhibitory Properties

Cited by 5 publications

References 54 publications

Color Coding for the Fragment-Based Docking, Design and Equilibrium Statistics of Protein-Binding ssRNAs

Color Coding for the Fragment-Based Docking, Design and Equilibrium Statistics of Protein-Binding ssRNAs

Chemically Modified Poly(A) Analogs Targeting PABP: Structure Activity Relationship and Translation Inhibitory Properties

Neoantigen vaccine nanoformulations based on Chemically synthesized minimal mRNA (CmRNA): small molecules, big impact

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