Belinda Abbott

Pursuing DHDPS: an enzyme of unrealised potential as a novel antibacterial target

Publisher: Royal Society of Chemistry (RSC)

Date: 2019

DOI: 10.1039/C9MD00107G

Abstract: DHDPS represents a novel enzyme target for the development of new antibiotics to combat multidrug resistance.

Recent progress towards an effective treatment of amyotrophic lateral sclerosis using the SOD1 mouse model in a preclinical setting

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.EJMECH.2016.02.048

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal and incurable neurodegenerative disorder. Motor neurone degeneration can be caused by genetic mutation but the exact etiology of the disease, particularly for sporadic illness, still remains unclear. Therapeutics which target known pathogenic mechanisms involved in ALS, such as protein aggregation, oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and mitochondria dysfunction, are currently being pursued in order to provide neuroprotection which may be able to slow down, or perhaps even halt, disease progression. This present review focuses on the compounds which have been recently evaluated using the SOD1 mouse model, the most widely used preclinical model for ALS research.

PI 3-kinase p110β: A new target for antithrombotic therapy

Publisher: Springer Science and Business Media LLC

Date: 17-04-2005

DOI: 10.1038/NM1232

Abstract: Platelet activation at sites of vascular injury is essential for the arrest of bleeding however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.

Enhancing allosteric inhibition of dihydrodipicolinate synthase through the design and synthesis of novel dimeric compounds

Publisher: Royal Society of Chemistry (RSC)

Date: 2023

DOI: 10.1039/D3MD00044C

Abstract: The synthesis of the first low micromolar dimeric inhibitor of E. coli DHDPS is reported.

A novel small molecule inhibitor of human Drp1

Publisher: Springer Science and Business Media LLC

Date: 13-12-2022

DOI: 10.1038/S41598-022-25464-Z

Abstract: Mitochondrial dynamin-related protein 1 (Drp1) is a large GTPase regulator of mitochondrial dynamics and is known to play an important role in numerous pathophysiological processes. Despite being the most widely used Drp1 inhibitor, the specificity of M i-1 towards human Drp1 has not been definitively proven and there have been numerous issues reported with its use including off-target effects. In our hands M i-1 showed varying binding affinities toward human Drp1, potentially impacted by compound aggregation. Herein, we sought to identify a novel small molecule inhibitor of Drp1. From an initial virtual screening, we identified DRP1i27 as a compound which directly bound to the human isoform 3 of Drp1 via surface plasmon resonance and microscale thermophoresis. Importantly, DRP1i27 was found to have a dose-dependent increase in the cellular networks of fused mitochondria but had no effect in Drp1 knock-out cells. Further analogues of this compound were identified and screened, though none displayed greater affinity to human Drp1 isoform 3 than DRP1i27. To date, this is the first small molecule inhibitor shown to directly bind to human Drp1.

Discovery, synthesis and exploration of N-benzylsulfonyl-2-phenylazepanes as inhibitors of Bim expression in a mouse embryonic fibroblast model

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.BIOORG.2022.105635

Abstract: Chronic activation of beta-adrenergic receptors by the sympathetic nervous system results in the apoptosis of cardiomyocytes. Due to the inability of cardiomyocytes to regenerate, this can result in heart failure. Upregulation of the pro-apoptotic protein Bim has been implicated as the cause of cardiomyocyte apoptosis. Beta blockers are the frontline drug used to negate this apoptotic pathway, as no direct inhibitors of Bim expression currently exist. Unfortunately, treatment of heart failure using beta blockers is not optimal. Therefore, direct inhibition of Bim expression is an attractive strategy to provide protection against stress-induced apoptosis of cardiomyocytes. Herein we explore a class of N-benzylsulfonyl-2-phenylazepanes to obtain anti-apoptotic compounds capable of reducing Bim expression levels to 7% of the control at 10 μM in cardiomyocytes under conditions of chronic beta-adrenergic receptor activation with little inhibitory effect upon protein kinase A activity and minimal toxicity.

Towards novel herbicide modes of action by inhibiting lysine biosynthesis in plants

Publisher: eLife Sciences Publications, Ltd

Date: 27-07-2021

DOI: 10.7554/ELIFE.69444

Abstract: Weeds are becoming increasingly resistant to our current herbicides, posing a significant threat to agricultural production. Therefore, new herbicides with novel modes of action are urgently needed. In this study, we exploited a novel herbicide target, dihydrodipicolinate synthase (DHDPS), which catalyses the first and rate-limiting step in lysine biosynthesis. The first class of plant DHDPS inhibitors with micromolar potency against Arabidopsis thaliana DHDPS was identified using a high-throughput chemical screen. We determined that this class of inhibitors binds to a novel and unexplored pocket within DHDPS, which is highly conserved across plant species. The inhibitors also attenuated the germination and growth of A. thaliana seedlings and confirmed their pre-emergence herbicidal activity in soil-grown plants. These results provide proof-of-concept that lysine biosynthesis represents a promising target for the development of herbicides with a novel mode of action to tackle the global rise of herbicide-resistant weeds.

Synthetic studies of the phosphatidylinositol 3-kinase inhibitor LY294002 and related analogues

Publisher: CSIRO Publishing

Date: 2003

DOI: 10.1071/CH03113

Abstract: Synthetic methodologies have been developed for the direct and high-yielding preparation of the phosphatidylinositol 3-kinase inhibitor LY294002. These methods are readily amenable to the efficient generation of analogues, which will facilitate a detailed investigation of this important family of enzymes.

Halocarbons as hydrogen bond acceptors: a spectroscopic study of haloethylbenzenes (PhCH2CH2X, X = F, Cl, Br) and their hydrate clusters

Publisher: Royal Society of Chemistry (RSC)

Date: 2018

DOI: 10.1039/C7CP07365H

Abstract: The hydrogen bond acceptor strength of a series of halocarbons is studied by electronic and vibrational spectroscopy.

Potent inhibitors of phosphatidylinositol 3 (PI3) kinase that have antiproliferative activity only when delivered as prodrug forms.

Publisher: Wiley

Date: 08-04-2013

DOI: 10.1002/CMDC.201200583

Abstract: Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl-substituted analogues were further derivatized as prodrugs resulting in restoration of cell-based activity. These data provide a conceptual model for development of tumor-targeting prodrug forms of cell-impermeable PI3K inhibitors.

Elaboration of a benzofuran scaffold and evaluation of binding affinity and inhibition of Escherichia coli DsbA: A fragment-based drug design approach to novel antivirulence compounds

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/J.BMC.2021.116315

A dual-target herbicidal inhibitor of lysine biosynthesis

Publisher: eLife Sciences Publications, Ltd

Date: 20-06-2022

DOI: 10.7554/ELIFE.78235

Abstract: Herbicides with novel modes of action are urgently needed to safeguard global agricultural industries against the damaging effects of herbicide-resistant weeds. We recently developed the first herbicidal inhibitors of lysine biosynthesis, which provided proof-of-concept for a promising novel herbicide target. In this study, we expanded upon our understanding of the mode of action of herbicidal lysine biosynthesis inhibitors. We previously postulated that these inhibitors may act as proherbicides. Here, we show this is not the case. We report an additional mode of action of these inhibitors, through their inhibition of a second lysine biosynthesis enzyme, and investigate the molecular determinants of inhibition. Furthermore, we extend our herbicidal activity analyses to include a weed species of global significance.

Multi‐Targeted Inhibition of an Essential Bacterial Enzyme

Publisher: Wiley

Date: 04-2018

DOI: 10.1096/FASEBJ.2018.32.1_SUPPLEMENT.810.3

Photochemical synthesis of benz[h]isoquinolines

Publisher: Elsevier BV

Date: 05-2008

DOI: 10.1016/J.TET.2008.03.066

Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation.

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C5OB02517F

Abstract: A series of 4-cyano-3-methylisoquinolines have been shown to inhibit parasite cytokinesis and erythrocyte invasion.

Peptide Nucleic Acid Monomers: A Convenient and Efficient Synthetic Approach to Fmoc/Boc Monomers

Publisher: CSIRO Publishing

Date: 2012

DOI: 10.1071/CH11471

Abstract: A convenient and cost-effective method for the synthesis of Fmoc/Boc-protected peptide nucleic acid monomers is described. The Fmoc/Boc strategy was developed in order to eliminate the solubility issues during peptide nucleic acid solid-phase synthesis, in particular that of the cytosine monomer, that occurred when using the commercialized Bhoc chemistry approach.

Molecular evolution of an oligomeric biocatalyst functioning in lysine biosynthesis.

Publisher: Springer Science and Business Media LLC

Date: 05-12-2017

DOI: 10.1007/S12551-017-0350-Y

A reversed-phase HPLC-based method for the assay of cyclic nucleotide phosphodiesterase activity

Publisher: Elsevier BV

Date: 04-2005

DOI: 10.1016/J.AB.2004.12.014

The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors

Publisher: MDPI AG

Date: 18-10-2019

DOI: 10.3390/MOLECULES24203756

Abstract: A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to EcDsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of EcDsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants (KD) of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors.

Synthesis and structure-activity relationship studies of 2,4-thiazolidinediones and analogous heterocycles as inhibitors of dihydrodipicolinate synthase

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.BMC.2021.116518

Abstract: Dihydrodipicolinate synthase (DHDPS), responsible for the first committed step of the diaminopimelate pathway for lysine biosynthesis, has become an attractive target for the development of new antibacterial and herbicidal agents. Herein, we report the discovery and exploration of the first inhibitors of E. coli DHDPS which have been identified from screening lead and are not based on substrates from the lysine biosynthesis pathway. Over 50 thiazolidinediones and related analogues have been prepared in order to thoroughly evaluate the structure-activity relationships against this enzyme of significant interest.

Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum

Publisher: Elsevier BV

Date: 06-2016

DOI: 10.1016/J.BMC.2016.03.048

Abstract: A series of isoquinolines have been evaluated in a homology model of Plasmodium falciparum Protein Kinase A (PfPKA) using molecular dynamics. Synthesis of these compounds was then undertaken to investigate their structure-activity relationships. One compound was found to inhibit parasite growth in an in vitro assay and provides a lead to further develop 3-methylisoquinoline-4-carbonitriles as antimalarial compounds. Development of a potent and selective PfPKA inhibitor would provide a useful tool to shed further insight into the mechanisms enabling malaria parasites to establish infection.

Synthesis of novel 1,2,5-oxadiazoles and evaluation of action against Acinetobacter baumannii

Publisher: Elsevier BV

Date: 12-2017

DOI: 10.1016/J.BMC.2017.08.015

Abstract: With multidrug resistant bacteria on the rise, novel antibiotics are becoming highly sought after. In 2008, eleven compounds were identified by high throughput screening as inhibitors of BasE, a key enzyme of the non-ribosomal peptide synthetase pathway found in Acinetobacter baumannii. Herein, we describe the preparation of four structurally similar heterocyclic lead compounds from that study, including one 1,2,5-oxadiazole. A further library of 30 analogues containing the oxadiazole moiety was then generated. All compounds were screened against Acinetobacter baumannii and their minimum inhibitory concentration data is reported, with (E)-3-(2-hydroxyphenyl)-N-(4-methyl-1,2,5-oxadiazol-3-yl)acrylamide 32 found to have an MIC of 0.5mM. This work provides the foundation for further investigation of 1,2,5-oxadizoles as novel inhibitors of A. baumannii.

A total synthesis of a highly N-methylated cyclodepsipeptide [2S,3S-Hmp]-aureobasidin L using solid-phase methods

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.TET.2014.02.036

Synthesis and effects of conjugated tocopherol analogues on peptide nucleic acid hybridisation.

Publisher: Royal Society of Chemistry (RSC)

Date: 2013

DOI: 10.1039/C3OB41613E

A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4

Publisher: Springer Science and Business Media LLC

Date: 16-07-2019

DOI: 10.1038/S41598-019-46500-5

Abstract: We developed a novel series of antimalarial compounds based on a 4-cyano-3-methylisoquinoline. Our lead compound MB14 achieved modest inhibition of the growth in vitro of the human malaria parasite, Plasmodium falciparum . To identify its biological target we selected for parasites resistant to MB14. Genome sequencing revealed that all resistant parasites bore a single point S374R mutation in the sodium (Na + ) efflux transporter PfATP4. There are many compounds known to inhibit PfATP4 and some are under preclinical development. MB14 was shown to inhibit Na + dependent ATPase activity in parasite membranes, consistent with the compound targeting PfATP4 directly. PfATP4 inhibitors cause swelling and lysis of infected erythrocytes, attributed to the accumulation of Na + inside the intracellular parasites and the resultant parasite swelling. We show here that inhibitor-induced lysis of infected erythrocytes is dependent upon the parasite protein RhopH2, a component of the new permeability pathways that are induced by the parasite in the erythrocyte membrane. These pathways mediate the influx of Na + into the infected erythrocyte and their suppression via RhopH2 knockdown limits the accumulation of Na + within the parasite hence protecting the infected erythrocyte from lysis. This study reveals a role for the parasite-induced new permeability pathways in the mechanism of action of PfATP4 inhibitors.

Efficacy of peptide nucleic acid and selected conjugates against specific cellular pathologies of amyotrophic lateral sclerosis

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/J.BMC.2016.02.022

Abstract: Cellular studies have been undertaken on a nonamer peptide nucleic acid (PNA) sequence, which binds to mRNA encoding superoxide dismutase 1, and a series of peptide nucleic acids conjugated to synthetic lipophilic vitamin analogs including a recently prepared menadione (vitamin K) analog. Reduction of both mutant superoxide dismutase 1 inclusion formation and endoplasmic reticulum stress, two of the key cellular pathological hallmarks in amyotrophic lateral sclerosis, by two of the prepared PNA oligomers is reported for the first time.

PDE2 inhibition by the PI3 kinase inhibitor LY294002 and analogues

Publisher: Elsevier BV

Date: 06-2004

DOI: 10.1016/J.BMCL.2004.03.043

Analysis of anti-PDE3 activity of 2-morpholinochromone derivatives reveals multiple mechanisms of anti-platelet activity

Publisher: Elsevier BV

Date: 02-2006

DOI: 10.1016/J.BMCL.2005.10.092

Abstract: A series of synthetic 2-morpholinochromones have been evaluated as inhibitors of platelet phosphodiesterase, PDE3A. While previous assertions about the anti-PDE3 activity of this class have been confirmed, in some cases the reported anti-platelet activities clearly derive from a non-PDE3 regulated mechanism. The potential utility of 2-morpholinochromones either as PDE3 inhibitors and/or anti-thrombotic agents thus remains only poorly examined.

La Trobe University

Location: Australia

View Organisation

Discovery Projects - Grant ID: DP0771578

Start Date: 01-2007

End Date: 12-2009

Amount: $374,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882977

Start Date: 09-2008

End Date: 12-2009

Amount: $600,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE210100083

Start Date: 04-2021

End Date: 09-2022

Amount: $777,493.00

Funder: Australian Research Council