Biology subjects

Zhan, C.-G.

Publications and source records attributed to Zhan, C.-G..

3 recordsLinked to original sources

bioRxiv2026

Identification of scavenger receptor BI as a scavenger of free heme that is essential for protection against hemolysis

Severe hemolysis is a life-threatening condition with limited therapeutic options. Although haptoglobin and hemopexin sequester hemoglobin and heme, these protective systems are rapidly saturated during acute hemolysis, leading to the accumulation of cytotoxic free heme. In this study, we identify scavenger receptor BI (SR-BI) as a critical mediator of free heme clearance. SR-BI binds heme and facilitates its hepatic uptake under pathological conditions. Mice lacking hepatic SR-BI exhibit impaired heme clearance and increased susceptibility to heme- and hemolysis-induced lethality. Pharmacological upregulation of hepatic SR-BI via imatinib or adenoviral delivery confers protection against heme toxicity. Using a humanized model of sickle cell disease (SCD), we further demonstrate that sickle hepatopathy significantly reduces hepatic SR-BI expression compared to non-SCD littermates, potentially increasing vulnerability to heme-induced injury. Notably, adenoviral-mediated SR-BI upregulation rescues SCD mice from heme toxicity. These findings reveal a previously unrecognized mechanism of heme detoxification via hepatic SR-BI and identify a promising therapeutic target for hemolytic disorders. One-Sentence SummaryIdentification of scavenger receptor BI as a targetable scavenger of heme in hemolysis

physiology↗

bioRxiv2025

Tunable nucleofugality in carbamoyl-bearing covalent cholinesterase inhibitors

A handful of carbamate warheads is utilised in chemical biology to target serine hydrolases. The following case study on cholinesterases is the first comprehensive structure-reactivity exploration of the carbamoyl warhead, rather than one-target-oriented structure-activity study, with in-depth profiling of diverse halogen, chalcogen, and nitrogen-based leaving groups (nucleofuges) that can tune warhead reactivity. With computational tools we correlated the experimentally observed reactivities with steric and electronic factors of the investigated warheads. QM/MM simulations considering the enzymatic environment explained how substitution of carbon for nitrogen in the leaving groups of compounds 26 and 28 through resonance stabilisation, inductive bond polarization, and acidity amplification lowered the reaction barrier and increased the reaction rate >360 million times, making compound 28 a covalent inhibitor. Our findings underline the complexity of covalent inhibition and demonstrate that multiple complementary methods are required to interpret and predict covalent behaviour. Additionally, even though carbamates typically act as slow substrates, we were able to slow down decarbamoylation to a point where inhibition became de facto irreversible. The most interesting O-isoxazol-3-yl carbamate warhead was further profiled against the wider human proteome and showed low off-target reactivity, making it useful in further drug discovery. By establishing structure-reactivity principles for carbamoyl warhead, this study provides a generalisable framework for the development of selective covalent inhibitors and activity-based probes across diverse targets.

pharmacology and toxicology↗

bioRxiv2022

Computational Prediction of Binding Affinities of Human Angiotensin Converting Enzyme-2 with SARS-CoV-2 Spike Protein Variants: Omicron Variants and Potentially Deleterious Mutations

The Omicron variant (BA.1) and its sub-variants of the SARS-CoV-2 virus which causes the COVID-19 disease continues to spread across the United States and the World at large. As new sub-variants of SARS-CoV-2 continue to proliferate, a reliable computational method of quickly determining the potential infectivity of these new variants is needed to assess their potential threat. In the present study, we have tested and validated an efficient computational protocol, which includes an efficient energy minimization and subsequent molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) calculation of the binding free energy between the SARS-CoV-2 spike protein and human angiotensin converting enzyme-2 (ACE2), to predict the binding affinities of these spike/ACE2 complexes based upon the calculated binding free energies and a previously calibrated linear correlation relationship. The predicted binding affinities are in good agreement with available experimental data including those for Omicron variants, suggesting that the predictions based on this protocol should be reasonable. Further, we have investigated several hundred potential mutations of both the wildtype and Omicron variants of the SARS-CoV-2 spike protein. Based on the predicted binding affinity data, we have identified several mutations that have the potential to vastly increase the binding affinity of the spike protein to ACE2 within both the wildtype and Omicron variants. Author SummaryAs well known, the coronavirus responsible for COVID-19 disease enters human cells through its spike protein binding with a human receptor protein known as angiotensin converting enzyme-2. So, the binding affinity between the spike protein and angiotensin converting enzyme-2 contributes to the infectivity of the coronavirus and its variants. In this study, we demonstrated that a generally applicable, fast and easy-to-use computational protocol was able to accurately predict the binding affinity of angiotensin converting enzyme-2 with spike protein of the currently known variants of the coronavirus. Hence, we believe that this computational protocol may be used to reliably predict the binding affinity of angiotensin converting enzyme-2 with spike protein of new variants to be identified in the future. Using this computational protocol, we have further examined a number of possible single mutations on the spike protein of both the wildtype and Omicron variants and predicted their binding affinity with angiotensin converting enzyme-2, demonstrating that several mutations have the potential to vastly increase the binding affinity of the spike protein to angiotensin converting enzyme-2.

biophysics↗