Martin J Stoermer

Martin J Stoermer
The University of Queensland | UQ · Institute for Molecular Bioscience

BSc (Hons), PhD (Sydney University)

About

117
Publications
4,957
Reads
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2,061
Citations
Introduction
My research interests centre on using molecular modelling and organic synthesis to find enzyme inhibitors relevant to human disease. Current focus is inhibition of flaviviral proteases. http://fairlie.imb.uq.edu.au/researchers.php?id=5 http://orcid.org/0000-0003-3445-2104
Additional affiliations
January 2000 - present
The University of Queensland
Position
  • Current Research
Description
  • Synthesis of inhibitors of the NS3 serine proteases from Dengue and West Nile Flaviviruses NMR spectroscopy Virtual screening Molecular modeling Inhibitors of human non-secretory phospholipase A2
June 1996 - December 1999
Monash University (Australia)
Position
  • Research Associate
July 1995 - June 1996
Technische Universität Clausthal
Position
  • Postdoctoral Research Fellow
Description
  • Industry-funded postdoctoral position
Education
January 1986 - November 1990
The University of Sydney
Field of study
  • Organometallic Chemistry

Publications

Publications (117)
Article
Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The o...
Article
Full-text available
The G protein coupled receptor (C3aR) for human inflammatory protein complement C3a is an important component of immunity, inflammatory and metabolic disease. A flexible compound (N2-[(2,2-diphenylethoxy)acetyl]-L-arginine, 4), known as a weak C3aR antagonist (IC50 µM), was transformed here into potent agonists (EC50 nM) of human macrophages (Ca(2+...
Article
Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-Me amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH prot...
Article
The Friedel–Crafts alkylation of furans by the Michael acceptor, b-nitrostyrene, is greatly accelerated by the use of the Lewis acid catalyst and solvent, 5 M lithium perchlorate in diethyl ether (LDPE).
Article
Full-text available
A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functiona...
Preprint
Full-text available
Homology models of the Papain-like protease (PLpro) from the novel coronavirus 2019-nCoV, formerly Wuhan coronavirus, were prepared from both SARS and MERS crystallographic templates. The SARS models were of higher quality. Mobile regions of the enzyme were studied using 100ns molecular dynamics
Preprint
Initial title Homology models of Wuhan Coronavirus 3CLpro Protease has been replaced with the more widely accepted 2019-nCoV naming. Full preprint and the homology models and details of model preparation are all available at the ChemRxiv link
Data
Data tables for the publication "Orally Absorbed Cyclic Peptides" containing physicochemical and pharmacokinetic properties for the compounds under review
Conference Paper
Template-assembled peptide loops, helices, sheets and nanofibres
Preprint
The selection of a core scaffold or template is of enormous importance in medicinal chemistry. Benzimidazoles are a recurring fragment in medicinal chemistry, and the 2-amino derivative is a versatile example in lead generation. Alkylated and acylated examples abound, however, alternative linkage chemistries leading do more diverse structures are n...
Article
The formal cycloaddition adduct of 1,4-benzoquinone with two equivalents of cyclopentadiene is a scaffold with two non-conjugated alkenes. Both alkenes undergo exo [4+2] cycloaddition with a diene to form a rigid U-shaped molecular cleft. Here we show experimental, computational and structural evidence that pi interactions between the alkenes affec...
Article
Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of pept...
Poster
Molecular Modelling of flaviviral proteases. Homology modelling and Cystal structure approaches
Conference Paper
discussing relative percentages of Australian Chemistry Academics, what they use Twitter for, Pros and Cons of the Technology
Article
Full-text available
Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory pro...
Article
Dengue Virus (DENV) infection is responsible for the world's most significant insect-borne viral disease. Despite an increasing global impact, there are neither prophylactic nor therapeutic options available for the effective treatment of DENV infection. An attractive target for antiviral drugs is the virally encoded trypsin-like serine protease (N...
Article
Full-text available
Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistan...
Poster
Toward more orally bioavailable inhibitors of phospholipase A(2) GIIA (pla2g2a) to treat chronic inflammation.
Article
Full-text available
The flavivirus nonstructural protein 5 (NS5) is a large protein that is structurally conserved among members of the genus, making it an attractive target for antiviral drug development. The protein contains a methyltransferase (MTase) domain and an RNA dependent RNA polymerase (POL) domain. Previous studies with dengue viruses have identified a gen...
Article
Based on bioinformatics interrogation of the genome, >500 mammalian protein kinases can be clustered within seven different groups. Of these kinases, the mitogen-activated protein kinase (MAPK) family forms part of the CMGC group of serine/threonine kinases that includes extracellular signal regulated kinases (ERKs), cJun N-terminal kinases (JNKs),...
Article
Thousands of metabolites are excreted in urine, and potentially can be detected in NMR spectra. Currently, NMR spectral information for about one thousand metabolites has been deposited in publicly available sources, limiting the identification of chemical compounds that are potential biomarkers for clinical and subclinical applications. This study...
Article
Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor in being self-activated, after pruning of the N-terminus by serine proteases like trypsin and tryptase. Short synthetic peptides corresponding to the newly exposed N-terminal hexapeptide sequence also activate PAR2 on immunoinflammatory, cancer and many normal cell types....
Conference Paper
Towards orally bioavailable peptides and peptidomimetics
Article
Vinylmercury compounds, vinylboronic acids and vinylstannanes undergo rapid metal-lead exchange with lead tetraacetate in deuterochloroform to generate vinyllead triacetates, which have been characterised by their 1H-1H and 207Pb-1H coupling constants. In addition, a number of divinyl and mixed aryl-vinyllead dicarboxylates have been prepared via b...
Conference Paper
NMR structure determination of a component of sheep urine and confirmation by sythesis
Article
The flaviviruses comprise a large group of related viruses, many of which pose a significant global human health threat, most notably the dengue viruses (DENV), West Nile virus (WNV) and yellow fever virus (YFV). Flaviviruses enter host cells via fusion of the viral and cellular membranes, a process mediated by the major viral envelope protein E as...
Article
Serine protease enzymes use a serine hydroxyl group to catalyze hydrolysis of polypeptides. They are important in immunity, blood clotting, digestion, and as therapeutic or diagnostic targets for cancer, diabetes, stroke, inflammatory diseases, and viral infections. Their inhibitors typically possess an electrophile that reacts with the nucleophili...
Article
Over the last decade, West Nile virus has spread rapidly via mosquito transmission from infected migratory birds to humans. One potential therapeutic approach to treating infection is to inhibit the virally encoded serine protease that is essential for viral replication. Here we report the crystal structure of the viral NS3 protease tethered to its...
Article
West Nile virus (WNV) has spread rapidly around the globe, efficiently crossing species from migrating birds into humans and other mammals. The viral protease NS2B-NS3 is important for WNV replication and recognizes dibasic substrate sequences common to other flaviviral proteases but different from most mammalian proteases. Potent inhibitors of WNV...
Article
An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB1 agonists. It is hoped that compounds of this type will have clinical utility in pain control and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of sev...
Article
Full-text available
The flavivirus NS2B/NS3 protease has received considerable attention as a target for the development of antiviral compounds. While substrate based inhibitors have been the primary focus to date, an approach focussing on NS2B cofactor displacement could prove to be an effective alternative. To understand better the role of the NS2B cofactor in prote...
Article
An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB(1) agonists. It is hoped that compounds of this type will have clinical utility in pain control, and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of...
Article
West Nile Virus (WNV) has spread rapidly during the last decade across five continents causing disease and fatalities in humans and mammals. It highlights the serious threat to both our health and the economy posed by viruses crossing species, in this case from migratory birds via mosquitoes to mammals. There is no vaccine or antiviral drug for tre...
Article
West Nile virus is a medically significant emerging pathogen for which there is no effective antiviral therapy. The viral protease encoded by NS2B and NS3 is an attractive target for development of an inhibitor and has been the focus of numerous studies. Most have employed recombinant proteases based on an expression strategy we developed which lin...
Article
Full-text available
West Nile Virus is becoming a widespread pathogen, infecting people on at least four continents with no effective treatment for these infections or many of their associated pathologies. A key enzyme that is essential for viral replication is the viral protease NS2B-NS3, which is highly conserved among all flaviviruses. Using a combination of molecu...
Article
Full-text available
Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro grow...
Article
In silico virtual screening for drug discovery has become a hot topic in medicinal chemistry research during the last 5 years, growing from a largely academic pursuit concerned principally with validating the methods used, to a major early-stage technique for lead discovery in the pharmaceutical industry. In this review we highlight a few recent su...
Article
A major chemical challenge is the structural mimicry of discontinuous protein surfaces brought into close proximity through polypeptide folding. We report the design, synthesis, and solution structure of a highly functionalized saddle-shaped macrocyclic scaffold, constrained by oxazoles and thiazoles,upporting two short peptide loops projecting ort...
Article
A major chemical challenge is the structural mimicry of discontinuous protein surfaces brought into close proximity through polypeptide folding. We report the design, synthesis, and solution structure of a highly functionalized saddle-shaped macrocyclic scaffold, constrained by oxazoles and thiazoles, supporting two short peptide loops projecting o...
Article
Full-text available
The flavivirus West Nile virus (WNV) has spread rapidly throughout the world in recent years causing fever, meningitis, encephalitis, and fatalities. Because the viral protease NS2B/NS3 is essential for replication, it is attracting attention as a potential therapeutic target, although there are currently no antiviral inhibitors for any flavivirus....
Article
Full-text available
West Nile Virus (WNV) is a mosquito-borne flavivirus with a rapidly expanding global distribution. Infection causes severe neurological disease and fatalities in both human and animal hosts. The West Nile viral protease (NS2B-NS3) is essential for post-translational processing in host-infected cells of a viral polypeptide precursor into structural...
Article
Human C5a is a plasma protein with potent chemoattractant and pro-inflammatory properties, and its overexpression correlates with severity of inflammatory diseases. C5a binds to its G protein-coupled receptor (C5aR) on polymorphonuclear leukocytes (PMNLs) through a high-affinity helical bundle and a low-affinity C terminus, the latter being solely...
Conference Paper
Cyclic peptide antagonists of the C5a receptor were studied by NMR, and compared to their bioactivities to help refine the antagonist-receptor binding model
Article
A high yielding synthesis of the pentacyclic diene-dione 1 has enabled investigation of its reactivity as a double dienophile in Diels-Alder [4+2] cycloadditions with isobenzofuran, leading to novel and highly symmetrical three-sided cavitands 3 and 4.
Article
The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for mimicking mu...
Article
[GRAPHICS] The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for m...
Article
Full-text available
Recombinant forms of the dengue 2 virus NS3 protease linked to a 40-residue co-factor, corresponding to part of NS2B, have been expressed in Escherichia coli and shown to be active against para-nitroanilide substrates comprising the P6-P1 residues of four substrate cleavage sequences. The enzyme is inactive alone or after the addition of a putative...
Poster
alpha ketoamides are commonly used as isosteric electrophilic warheads in the synthesis of peptide inhibitors of serine proteases. These compounds are unstable in base and hydrolyse at the position between the P1 isostere and the P1' residue
Article
Epibatidine (1) is a recently discovered trace alkaloid found in the skin of a Latin-American poisonous frog. Its remarkably high analgetic activity is accompanied by high toxicity. Therefore, in order to tune its biological activity, a convergent and efficient synthetic pathway was sought to synthesize epibatidine derivatives with different (het)a...