Biology subjects

Jang, S. K.

Publications and source records attributed to Jang, S. K..

3 recordsLinked to original sources

bioRxiv2026

Structure-guided design of a CD81-binding mini-protein that blocks hepatitis C virus entry

Despite the success of direct-acting antivirals, preventing hepatitis C virus (HCV) reinfection remains a critical global challenge. To address this, we leveraged deep learning-based de novo protein design to engineer mini-proteins targeting the large extracellular loop (LEL) of the HCV co-receptor CD81. These mini-proteins are predicted to precisely dock into CD81-LEL, occluding the critical binding interface required for the HCV E2 glycoprotein. Through biophysical screening, we identified mini-19, a lead candidate with sub-nanomolar affinity (KD = 0.5 nM) and high thermostability up to 95{degrees}C. Flow cytometry and super-resolution imaging confirmed that mini-19 specifically recognizes the native topology of CD81 on cells and extracellular vesicles. Functionally, mini-19 neutralized HCVcc infection (IC50 = 1.2 nM). Molecular dynamics simulations demonstrated that mini-19 acts as a structural clamp, restricting the fusogenic conformational plasticity of the receptor. By targeting a conserved host factor rather than the rapidly mutating viral envelope, mini-19 provides a high genetic barrier to resistance. Beyond offering a prophylactic strategy against HCV, our findings establish a stable biologic platform for targeting tetraspanin-enriched microdomains and modulating host-pathogen interactions.

bioengineering↗

bioRxiv2022

Activated interstitial macrophages are a predominant target of viral takeover and focus of inflammation in COVID-19 initiation in human lung

Early stages of deadly respiratory diseases such as COVID-19 have been challenging to elucidate due to lack of an experimental system that recapitulates the cellular and structural complexity of the human lung while allowing precise control over disease initiation and systematic interrogation of molecular events at cellular resolution. Here we show healthy human lung slices cultured ex vivo can be productively infected with SARS-CoV-2, and the cellular tropism of the virus and its distinct and dynamic effects on host cell gene expression can be determined by single cell RNA sequencing and reconstruction of "infection pseudotime" for individual lung cell types. This revealed that the prominent SARS-CoV-2 target is a population of activated interstitial macrophages (IMs), which as infection proceeds accumulate thousands of viral RNA molecules per cell, comprising up to 60% of the cellular transcriptome and including canonical and novel subgenomic RNAs. During viral takeover of IMs, there is cell-autonomous induction of a pro-fibrotic program (TGFB1, SPP1), and an inflammatory program characterized by the early interferon response, chemokines (CCL2, 7, 8, 13, CXCL10) and cytokines (IL6, IL10), along with destruction of cellular architecture and formation of dense viral genomic RNA bodies revealed by super-resolution microscopy. In contrast, alveolar macrophages (AMs) showed neither viral takeover nor induction of a substantial inflammatory response, although both purified AMs and IMs supported production of infectious virions. Spike-dependent viral entry into AMs was neutralized by blockade of ACE2 or Sialoadhesin/CD169, whereas IM entry was neutralized only by DC-SIGN/CD209 blockade. These results provide a molecular characterization of the initiation of COVID-19 in human lung tissue, identify activated IMs as a prominent site of viral takeover and focus of inflammation and fibrosis, and suggest therapeutic targeting of the DC-SIGN/CD209 entry mechanism to prevent IM infection, destruction and early pathology in COVID-19 pneumonia. Our approach can be generalized to define the initiation program and evaluate therapeutics for any human lung infection at cellular resolution.

genomics↗

bioRxiv2017

Computational docking reveals evolutionary conservation of a specific interaction between 15d-Prostaglandin-J2 and eIF4A.

15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) is anti-inflammatory/antineoplastic prostaglandin which functions through covalent binding to cysteine residues of various target proteins. We previously showed that 15d-PGJ2 mediated anti-inflammatory responses are dependent on the translational inhibition through its interaction with eIF4A. Binding of 15d-PGJ2 to eIF4A specifically blocks the interaction between eIF4G and eIF4A leads to the formation of stress granules (SGs), which cluster mRNAs with inhibited translation. Here we show that the binding between 15d-PGJ2 and eIF4A specifically blocks the interaction between the MIF4G domain of eIF4G and eIF4A. To reveal the mechanism of this interaction, we used computational simulation-based docking studies and identified that the carboxyl tail of 15d-PGJ2 could stabilize the binding of 15d-PGJ2 to eIF4A through arginine 295 of eIF4A, which is the first suggestion that the 15d-PGJ2 tail play a physiological role. Interestingly, the putative 15d-PGJ2 binding site on eiF4A is conserved across many species, suggesting a biological role. Our data propose that studying 15d-PGJ2 and its targets will may uncover new therapeutic approaches in anti-inflammatory drug discovery.

molecular biology↗