Biology subjects

Pei, X. Y.

Publications and source records attributed to Pei, X. Y..

3 recordsLinked to original sources

bioRxiv2025

Rationally Designed, ACE2 Mimetic Binder to the SARS Cov-2 Associated Spike Protein for COVID-19 Therapeutics and Beyond

We have developed a 23 residue, optimized helical peptide biomimetic from the SARS-CoV-2 Spike protein binding partner ACE2 that demonstrated a Therapeutic Index (TI) of >[~]20 in authentic viral cell challenge assays, including WT and Omicron strains. The therapeutic is an optimized "peptide decoy" based on the viruss human cell target ACE2 and, as such, may have more general applicability across coronavirus family members that use ACE2 for cellular entry. We experimentally verify a comprehensive, rational optimization strategy of the peptide through improved binding, helical content, and solubility from its native sequence. These techniques may have general applicability for helical peptide optimization for other therapeutic targets as well. Importantly, techniques also exist for protecting helical peptides in vivo for improved delivery. Peptides are readily modifiable with single residue substitutions for quick response to mutated targets, and they typically have relatively low toxicity and ease of manufacturing, making peptides extremely attractive as biological therapeutics against viral pathogens. The general concept of using peptide decoys across other viral human cell targets is also discussed. Author SummaryAlthough the COVID-19 pandemic has ended, SARS-CoV-2 virus still causes hundreds of deaths each week world-wide. The virus uses a human cell receptor called ACE2 to latch on and enter cells. Here, the small critical attachment segment of ACE2 is developed as a "decoy" molecule thereby protecting host cells and significantly reducing viral replication, which is the role of a therapeutic agent. The effective segment in this case is called a helical peptide and it was optimized for better binding, solubility, and stability using rational methods based on our understanding of this class of molecule. Moreover, future viruses from this family of coronaviruses may likely use ACE2 as their host cell receptor, as recently demonstrated in the Middle Eastern Respiratory Syndrome Virus of bats and, therefore, the ACE2 decoy therapeutic may have future applications as well. Development of a broader range of decoy molecules for different viruses using different human cell receptors may represent a forward-thinking approach to prepare for future pandemics and outbreaks.

microbiology↗

bioRxiv2021

The decrotonylase FoSir5 facilitates mitochondrial metabolic state switching in conidial germination of Fusarium oxysporum

Fusarium oxysporum is one of the most important pathogenic fungi with a broad range of plant and animal hosts. The first key step of its infection cycle is conidial germination, but there is limited information available on the molecular events supporting this process. We show here that germination is accompanied by a sharp decrease in expression of FoSir5, an ortholog of the human lysine deacetylase SIRT5. We observe that FoSir5 decrotonylates a subunit of the fungal pyruvate dehydrogenase complex (FoDLAT) at K148, resulting in inhibition of the activity of the complex in mitochondria. Moreover, FoSir5 decrotonylates histone H3K18, leading to a downregulation of transcripts encoding enzymes of aerobic respiration pathways. Thus, the activity of FoSir5 coordinates regulation in different organelles to steer metabolic flux through respiration. As ATP content is positively related to fungal germination, we propose that FoSir5 negatively modulates conidial germination in F. oxysporum through its metabolic impact. These findings provide insights into the multifaceted roles of decrotonylation, catalysed by FoSir5, that support conidial germination in F. oxysporum.

microbiology↗

bioRxiv2018

Architectural principles for Hfq/Crc-mediated regulation of gene expression

The global regulator Hfq facilitates the action of regulatory RNAs in post-transcription gene regulation in many Gram-negative bacteria. In Pseudomonas aeruginosa, Hfq, in conjunction with the catabolite repression protein Crc, was shown to form a complex that directly inhibits translation of target transcripts during carbon catabolite repression. Here, we describe and validate high-resolution cryo-EM structures of the cooperative assembly of Hfq and Crc bound to a translation initiation site. The core assembly is formed through interactions of two cognate RNAs, two Hfq hexamers and a Crc pair. Additional Crc protomers can be recruited to form higher-order assemblies with demonstrated in vivo activity. The structures indicate a distinctive RNA conformation and a pattern of repeating motifs that confer regulatory function. This study not only reveals for the first time how Hfq cooperates with a partner protein to regulate translation but also provides a novel structural basis to explain how an RNA code can guide global regulators to interact cooperatively and regulate many different RNA targets.

biophysics↗