Biology subjects

Chang, J. S.

Publications and source records attributed to Chang, J. S..

4 recordsLinked to original sources

bioRxiv2024

Discovery of orally active SARS-CoV-2 papain-like protease (PLpro) inhibitors

Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

microbiology↗

bioRxiv2023

Preclinical Characterization of the Omicron XBB.1.5-Adapted BNT162b2 COVID-19 Vaccine

As SARS-CoV-2 continues to evolve, increasing in its potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity to protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine, which contains the same mRNA backbone as the original BNT162b2 vaccine, modified by the incorporation of XBB.1.5-specific sequence changes in the encoded prefusion-stabilized SARS-CoV-2 spike protein (S(P2)). Biophysical characterization of Omicron XBB.1.5 S(P2) demonstrated that it maintains a prefusion conformation that adopts a flexible and predominantly open one-RBD-up state, with high affinity binding to the human ACE-2 receptor. When administered as a 4th dose in BNT162b2-experienced mice, the monovalent Omicron XBB.1.5 vaccine elicited substantially higher serum neutralizing titers against pseudotyped viruses of Omicron XBB.1.5, XBB.1.16, XBB.1.16.1, XBB.2.3, EG.5.1 and HV.1 sublineages and the phylogenetically distant BA.2.86 lineage than the bivalent Wild Type + Omicron BA.4/5 vaccine. Similar trends were observed against Omicron XBB sublineage pseudoviruses when the vaccine was administered as a 2-dose primary series in naive mice. Strong S-specific Th1 CD4+ and IFN{gamma}+ CD8+ T cell responses were also observed. These findings, together with prior experience with variant-adapted vaccine responses in preclinical and clinical studies, suggest that the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine is anticipated to confer protective immunity against dominant SARS-CoV-2 strains. ONE-SENTENCE SUMMARYThe monovalent Omicron XBB.1.5-adapted BNT162b2 mRNA vaccine encodes a prefusion-stabilized spike immunogen that elicits more potent neutralizing antibody responses against homologous XBB.1.5 and other circulating sublineage pseudoviruses compared to the bivalent Wild Type + Omicron BA.4/5 BNT162b2 vaccine, thus demonstrating the importance of annual strain changes to the COVID-19 vaccine.

immunology↗

bioRxiv2022

Accurate models of substrate preferences of post-translational modification enzymes from a combination of mRNA display and deep learning

Promiscuous post-translational modification (PTM) enzymes often display non-obvious substrate preferences by acting on diverse yet well-defined sets of peptides and/or proteins. Thorough understanding of substrate fitness landscapes for promiscuous PTM enzymes is important because they play key roles in many areas of contemporary science, including natural product biosynthesis, molecular biology and biotechnology. Here, we report the development of an integrated platform for accurate profiling of substrate preferences for PTM enzymes. The platform features a combination of i) mRNA display with next generation sequencing as an ultrahigh throughput technique for data acquisition and ii) deep learning for data analysis. The high accuracy (>0.99 in each of two studies) and generalizability of the resulting deep learning models enables comprehensive analysis of enzymatic substrate preferences. The models can be utilized to quantify fitness across sequence space, map modification sites, and identify important amino acids in the substrate. To benchmark the platform, we perform substrate specificity profiling of a Ser dehydratase (LazBF) and a Cys/Ser cyclodehydratase (LazDEF), two enzymes from the lactazole biosynthesis pathway. In both studies, our results point to highly complex enzymatic preferences, which, particularly for LazBF, cannot be reduced to a set of simple rules. The ability of the constructed models to dissect and analyze such complexity suggests that the developed platform can facilitate the wider study of PTM enzymes.

biochemistry↗

bioRxiv2021

A chemical-genetic map of the pathways controlling drug potency in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Treatment efficacy is limited by Mtbs intrinsic drug resistance, as well as its ability to evolve acquired resistance to all antituberculars in clinical use. A deeper understanding of the bacterial pathways that govern drug efficacy could facilitate the development of more effective therapies to overcome resistance, identify new mechanisms of acquired resistance, and reveal overlooked therapeutic opportunities. To define these pathways, we developed a CRISPR interference chemical-genetics platform to titrate the expression of Mtb genes and quantify bacterial fitness in the presence of different drugs. Mining this dataset, we discovered diverse and novel mechanisms of intrinsic drug resistance, unveiling hundreds of potential targets for synergistic drug combinations. Combining chemical-genetics with comparative genomics of Mtb clinical isolates, we further identified numerous new potential mechanisms of acquired drug resistance, one of which is associated with the emergence of a multidrug-resistant tuberculosis (TB) outbreak in South America. Lastly, we make the unexpected discovery of an "acquired drug sensitivity." We found that the intrinsic resistance factor whiB7 was inactivated in an entire Mtb sublineage endemic to Southeast Asia, presenting an opportunity to potentially repurpose the macrolide antibiotic clarithromycin to treat TB. This chemical-genetic map provides a rich resource to understand drug efficacy in Mtb and guide future TB drug development and treatment.

microbiology↗