A5045511261- Chemical Synthesis and Analysis
- Biochemical and Molecular Research
- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- Blood Coagulation and Thrombosis Mechanisms
- HIV/AIDS drug development and treatment
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Peptidase Inhibition and Analysis
- Pneumocystis jirovecii pneumonia detection and treatment
- RNA and protein synthesis mechanisms
- Venomous Animal Envenomation and Studies
- Molecular Sensors and Ion Detection
- Advanced biosensing and bioanalysis techniques
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Calpain Protease Function and Regulation
- Diabetes Treatment and Management
- Adenosine and Purinergic Signaling
- Redox biology and oxidative stress
- Advanced NMR Techniques and Applications
- RNA regulation and disease
- Analytical Chemistry and Sensors
- Sulfur Compounds in Biology
- Ion Channels and Receptors
- Neurological Disease Mechanisms and Treatments
Monash University
2014-2024
Science for Life Laboratory
2024
Uppsala University
2020-2024
Turing Institute
2023
British Library
2023
The Alan Turing Institute
2023
Australian Research Council
2016
Starpharma (Australia)
2009
Therapeutic targeting of the neurokinin 1 receptor in endosomes provides efficacious and prolonged pain relief.
Proteases that cleave protease-activated receptor-2 (PAR(2)) at Arg(36)↓Ser(37) reveal a tethered ligand binds to the cleaved receptor. PAR(2) activates transient receptor potential (TRP) channels of nociceptive neurons induce neurogenic inflammation and pain. Although proteases non-canonical sites can trigger distinct signaling cascades, functional importance PAR(2)-biased agonism is uncertain. We investigated whether neutrophil elastase, biased agonist PAR(2), causes pain by activating...
Structural studies of proteins and protein-ligand complexes by nuclear magnetic resonance (NMR) spectroscopy can be greatly enhanced site-specific attachment lanthanide ions to create paramagnetic centers. In particular, pseudocontact shifts (PCS) generated lanthanides contain important unique long-range structure information. Here, we present a high-affinity binding tag that attached single cysteine residues proteins. The new has many advantageous features are not available in this...
Pseudocontact shifts (PCS) from paramagnetic lanthanide ions present powerful long-range structural restraints for biology by NMR spectroscopy, but site-specific tagging of proteins with lanthanides remains a challenge, as most the available tags require single cysteine residues. We show that cyclen-based can be attached to in manner Cu(I)-catalyzed azide–alkyne cycloaddition genetically encoded p-azido-l-phenylalanine residue tether proved sufficiently short and rigid observation PCSs...
Re(I) tricarbonyl polypyridine-based complexes are particularly attractive metal in the field of inorganic chemical biology due to their luminescent properties, ease conjugation targeting biomolecules, and possibility prepare "hot" 99mTc analogues for radioimaging. In this study, we prepared characterized a novel, "clickable" complex, [Re(2,2′-bipyridine)(3-ethynylpyridine)(CO)3](BF4) ([Re(CO)3(bipy)(py-alkyne)](BF4)), exhibiting characteristic properties moderate cytotoxicity general class...
Abstract Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes formation 7,8‐dihydropteroate (DHPt) from 6‐hydroxymethyl‐7,8‐dihydropterin pyrophosphate (DHPPP) and para ‐aminobenzoic acid (pABA). DHPS long‐standing target sulfonamide class antibiotics that compete with pABA. In wake sulfa drug resistance, targeting structurally rigid (and more conserved) pterin site has been proposed as alternate strategy to inhibit in wild‐type resistant strains....
A wide range of drug targets can be effectively modulated by peptides and macrocycles. Unfortunately, the size polarity these compounds prevents them from crossing cell membrane to reach target sites in cytosol. As such, do not conform standard measures drug-likeness exist beyond rule-of-five space. In this work, we investigate whether prodrug moieties that mask hydrogen bond donors applied domain improve permeation macrocyclic compounds. Using a cyclic peptide model, show masking natural...
Granzyme K (GzmK) is a tryptic member of the granzyme family chymotrypsin-like serine proteases produced by cells immune system. Previous studies have indicated that GzmK activates protease-activated receptor 1 (PAR1) enhancing activation monocytes and wound healing in endothelial cells. Here, we show using peptides full length proteins and, to lesser extent related protease GzmA, are capable activating PAR1 PAR2. These cleavage events occur at canonical arginine P1 residue involve exosite...
The ability to predict cell-permeable candidate molecules has great potential assist drug discovery projects. Large that lie beyond the Rule of Five (bRo5) are increasingly important as candidates and tool for chemical biology. However, such large usually do not cross cell membranes cannot access intracellular targets or be developed orally bioavailable drugs. Here, we describe a random forest (RF) machine learning model prediction passive membrane permeation rates using set over 1000 bRo5...
Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired syndrome and potentially death. Although treatments are available prevent its progression, HIV-1 remains major burden on health resources worldwide. Continued emergence drug-resistance mutations drives need for novel drugs can inhibit replication through new pathways. The viral protein reverse transcriptase (RT) plays fundamental role in cycle, multiple approved...
Diverse proteases cleave protease-activated receptor-2 (PAR2) on primary sensory neurons and epithelial cells to evoke pain inflammation. Trypsin tryptase activate PAR2 by a canonical mechanism that entails cleavage within the extracellular N-terminus revealing tethered ligand activates cleaved receptor. Cathepsin-S elastase are biased agonists at different sites distinct signalling pathways. Although is therapeutic target for inflammatory painful diseases, divergent mechanisms of...
As the second essential enzyme of folate biosynthetic pathway, potential antimicrobial target, HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase), catalyzes Mg(2+-)dependant transfer pyrophosphate from cofactor (ATP) to substrate, 6-hydroxymethyl-7,8-dihydropterin. Recently, we showed that 8-mercaptoguanine (8-MG) bound at substrate site (KD ∼13 µM), inhibited S. aureus (SaHPPK) (IC50 ∼ 41 and determined structure SaHPPK/8-MG complex. Here present synthesis a series guanine...
SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated targeted for degradation. Inhibition of this interaction increases levels, consequently cellular (NO) concentrations, has been proposed as a potential strategy killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 CP2) potent inhibitors murine SPSB–iNOS interaction. In study, we report...
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes pyrophosphoryl transfer ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified characterized binding S8-functionalized derivative (3). X-ray structures both SaHPPK/3/cofactor analogue ternary SaHPPK/cofactor...
A key component of a digital twin is the monitored data, communicated from physical system to virtual representation, for visualization and simulation. Yet little attention has been paid practicalities working with live-streamed data. Strategies are required providing continuous access storage, processing data indeterminate quality, ensuring long-term sustainability communication systems. This paper describes design infrastructure, 3D interpretation tools, model development implementation,...
The IRAP inhibition of the macrocyclic peptide, HA-08 has been explored by analogue design coupled to molecular dynamics analysis.
The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 family and highly expressed in many tissues, including neocortex hippocampus brain. IRAP involved various physiological functions has been identified as a receptor for endogenous hexapeptide Angiotensin IV (Ang IV). Binding Ang inhibits enzymatic activity proven to enhance learning memory animal models. macrocyclic compound 9 (C9) potent synthetic inhibitor developed from previously reported HA08. In this study, we...
The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 family and highly expressed in many tissues, including neocortex hippocampus brain. IRAP involved various physiological functions has been identified as a receptor for endogenous hexapeptide Angiotensin IV (Ang IV). binding Ang inhibits enzymatic activity proven to enhance learning memory animal models. macrocyclic compound 9 (C9) potent synthetic inhibitor developed from previously reported HA08. In this study, we...