Biology subjects

Coleman, D.

Publications and source records attributed to Coleman, D..

4 recordsLinked to original sources

bioRxiv2023

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro) is a highly conserved and essential protease that plays key roles in viral replication and pathogenesis among various CoVs, representing one of the most attractive drug targets for antiviral drug development. Traditional antiviral drug development strategies focus on the pursuit of high-affinity binding inhibitors against MPro. However, this approach often suffers from issues such as toxicity, drug resistance, and a lack of broad-spectrum efficacy. Targeted protein degradation represents a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. Here we leverage the proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Our previously developed MPro inhibitors MPI8 and MPI29 were used as MPro ligands to conjugate a CRBN E3 ligand, leading to compounds that can both inhibit and degrade SARS-CoV-2 MPro. Among them, MDP2 was demonstrated to effectively reduce MPro protein levels in 293T cells (DC50 = 296 nM), relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells, concurrently demonstrating potent anti-SARS-CoV-2 activity (EC50 = 492 nM). This proof-of-concept study highlights the potential of PROTAC-mediated targeted protein degradation of MPro as an innovative and promising approach for COVID-19 drug discovery.

biochemistry↗

bioRxiv2023

The AusTraits Plant Dictionary

Traits with intuitive names, a clear scope and explicit description are essential for all trait databases. Reanalysis of data from a single database, or analyses that integrate data across multiple databases, can only occur if researchers are confident the trait concepts are consistent within and across sources. The lack of a unified, comprehensive resource for plant trait definitions has previously limited the utility of trait databases. Here we describe the AusTraits Plant Dictionary (APD), which extends the trait definitions included in the new trait database AusTraits. The development process of the APD included three steps: review and formalisation of the scope of each trait and the accompanying trait description; addition of trait meta-data; and publication in both human and machine-readable forms. Trait definitions include keywords, references and links to related trait concepts in other databases, and the traits are grouped into a hierarchy for easy searching. As well as improving the usability of AusTraits, the Dictionary will foster the integration of trait data across global and regional plant trait databases.

ecology↗

bioRxiv2023

An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease

Main protease (MPro) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 C atom in an MPro substrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the MPro catalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent MPro inhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC50 value in inhibiting SARS-CoV-2 from infecting ACE2+ A549 cells and a selectivity index of 875. The crystallography analyses of MPro bound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent MPro inhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 MPro as therapeutics for COVID-19.

biochemistry↗

bioRxiv2021

Vulnerability to cavitation is linked to home climate precipitation across eight eucalypt species

Vulnerability to cavitation in leaves is the result of highly adaptive anatomical and physiological traits that can be linked to water availability in a species climate of origin. Despite similar gross leaf morphology, eucalypt species are often confined to specific climate envelopes across the variable rainfall environments of Australia. In this study, we investigate how the progression of cavitation differs among eucalypts and whether this is related to other hydraulic and physical leaf traits. We used the Optical Visualisation technique to capture cavitation progression across the leaves of eight eucalypt species (Angophora crassifolia, Corymbia tessellaris, Eucalyptus atrata, Eucalyptus grandis, Eucalyptus laevopinea, Eucalyptus longifolia, Eucalyptus macrandra, Eucalyptus tereticornis) from a wide range of climates and grown in a common garden setting. Vulnerability to cavitation, represented by the leaf water potential required for 50% cavitation of leaf vessels, varied significantly among species (-3.48 MPa to -8.25 MPa) and correlated linearly with home climate precipitation and leaf SLA (R2 of 0.64 and 0.75, respectively). P12-P88, the range of water potentials between which 12% to 88% of cavitation occurs, was decoupled from P50 but also correlated with leaf SLA (R2 of 0.72). We suggest the magnitude of P12-P88 may be representative of a species drought strategy - a large P12-P88 signifying leaves that exhibit drought tolerance (retention of leaves under drought conditions) and a small P12-P88 signifying drought avoidance (leaf shedding after a threshold of drought is reached). Our results agree with other studies that highlight these cavitation metrics as genetically fixed traits. Turgor loss point, on the other hand, may be more plastic, as evidenced by the low variability of this trait across these eucalypt species grown in a common garden environment. Further study will help to establish the SLA-related anatomical traits that impart cavitation resistance and to extend these conclusions to a greater number of species and home climates.

plant biology↗