Cyclic peptides targeting the SARS-CoV-2 programmed ribosomal frameshifting RNA from a multiplexed phage display library

Chemical Science, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

RNA provides the genetic blueprint for many pathogenic viruses, including SARS-CoV-2. The propensity of to fold into specific tertiary structures enables biomolecular recognition cavities and crevices suited binding drug-like molecules. Despite increasing interest in as a target chemical biology therapeutic applications, development molecules that recognize with high affinity specificity represents significant challenge. Here, we report strategy discovery selection RNA-targeted macrocyclic peptides derived from combinatorial libraries peptide macrocycles displayed by bacteriophages. Specifically, platform phage display organo-peptide hybrids (MOrPH-PhD) was combined diverse set non-canonical amino acid-based cyclization modules produce large 10

Язык: Английский

---

Decoding the genome of SARS-CoV-2: a pathway to drug development through translation inhibition

RNA Biology, Год журнала: 2024, Номер 21(1), С. 1 - 18

Опубликована: Дек. 4, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the disease 2019 (COVID-19) pandemic and is continuously spreading globally. continuous emergence of new SARS-CoV-2 variants keeps posing threats, highlighting need for fast-acting, mutation-resistant broad-spectrum therapeutics. Protein translation vital replication, producing early non-structural proteins RNA replication transcription, late structural virion assembly. Targeted blocking viral protein thus a potential approach to developing effective anti-SARS-CoV-2 drugs. SARS-CoV-2, as an obligate parasite, utilizes host's machinery. Translation-blocking strategies that target mRNA, especially those its conserved elements are generally preferred. In this review, we discuss current understanding translation, important motifs structures involved in regulation. We also through degradation or element dysfunction.

Язык: Английский

---

Tying the knot: Unraveling the intricacies of the coronavirus frameshift pseudoknot

PLoS Computational Biology, Год журнала: 2024, Номер 20(5), С. e1011787 - e1011787

Опубликована: Май 7, 2024

Understanding and targeting functional RNA structures towards treatment of coronavirus infection can help us to prepare for novel variants SARS-CoV-2 (the virus causing COVID-19), any other coronaviruses that could emerge via human-to-human transmission or potential zoonotic (inter-species) events. Leveraging the fact all use a mechanism known as −1 programmed ribosomal frameshifting (−1 PRF) replicate, we apply algorithms predict most energetically favourable secondary (each nucleotide involved in at one pairing) may be regulating PRF event coronaviruses, especially SARS-CoV-2. We compute previously unknown stable structure predictions frameshift site hierarchical folding, biologically motivated framework where initial non-crossing folds first, followed by subsequent, possibly crossing (pseudoknotted), structures. Using mutual information from 181 sequences, conjunction with algorithm KnotAli, different coronaviruses. then utilize Shapify obtain guided sequence-specific genome-wide experimental data. build on our previous investigation singular 68 nt element sequence, using 132 extended sequences including covariation information. Previous investigations have not applied folding length sequences. By doing so, simulate effects ribosome interaction site, providing insight biological function. contribute in-depth discussion contextualize dual-graph motifs SARS-CoV-2, highlighting energetic stability identified 3_8 motif alongside dominant 3_3 3_6 (native-type) combination thermodynamic methods sequence covariation, suggest function attenuator hairpin pseudoknotted base pairing. While certain is consistent, pairs form which indicate conformational switching between two

Язык: Английский

---

Tying the Knot: Unraveling the Intricacies of the Coronavirus Frameshift Pseudoknot

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 28, 2023

Understanding and targeting functional RNA structures towards treatment of coronavirus infection can help us to prepare for novel variants SARS-CoV-2 (the virus causing COVID-19), any other coronaviruses that could emerge via human-to-human transmission or potential zoonotic (inter-species) events. Leveraging the fact all use a mechanism known as -1 programmed ribosomal frameshifting (-1 PRF) replicate, we apply algorithms predict most energetically favourable secondary (each nucleotide involved in at one pairing) may be regulating PRF event coronaviruses, especially SARS-CoV-2. We compute previously unknown stable structure predictions frameshift site hierarchical folding, biologically motivated framework where initial non-crossing folds first, followed by subsequent, possibly crossing (pseudoknotted), structures. Using mutual information from 181 sequences, conjunction with algorithm KnotAli, different coronaviruses. then utilize Shapify obtain guided sequence-specific genome-wide experimental data. build on our previous investigation singular 68 nt element sequence, using 132 extended sequences including covariation information. Previous investigations have not applied folding length sequences. By doing so, simulate effects ribosome interaction site, providing insight biological function. contribute in-depth discussion contextualize dual-graph motifs SARS-CoV-2, highlighting energetic stability identified 3_8 motif alongside dominant 3_3 3_6 (native-type) Integrating data within minimum free energy (MFE) provides distill relationship between In particular, fully categorizing supports identification transitions critical targets future therapeutic research.

Язык: Английский

---