Lara Malins

A Rapid and Mild Sulfation Strategy Reveals Conformational Preferences in Therapeutically Relevant Sulfated Xylooligosaccharides

Publisher: Wiley

Date: 28-05-2021

DOI: 10.1002/CHEM.202100527

Abstract: Although sulfated xylooligosaccharides are promising therapeutic leads for a multitude of afflictions, the structural complexity and heterogeneity of commercially deployed forms (e. g. Pentosan polysulfate 1 ) complicates their path to further clinical development. We describe herein the synthesis of the largest homogeneous persulfated xylooligomers prepared to date, comprising up to eight xylose residues, as standards for biological studies. Near quantitative sulfation was accomplished using a remarkably mild and operationally simple protocol which avoids the need for high temperatures and a large excess of the sulfating reagent. Moreover, the sulfated xylooligomer standards so obtained enabled definitive identification of a pyridinium contaminant in a s le of a commercially prepared Pentosan drug and provided significant insights into the conformational preferences of the constituent persulfated monosaccharide residues. As the spatial distribution of sulfates is a key determinant of the binding of sulfated oligosaccharides to endogenous targets, these findings have broad implications for the advancement of Pentosan‐based treatments.

Limitations in the inverse association between psychological resilience and depression in prostate cancer patients experiencing chronic physiological stress

Publisher: Wiley

Date: 08-2018

DOI: 10.1002/PON.4496

Abstract: To investigate the effect of chronic stress as measured in cortisol concentrations upon the association between psychological resilience (PR) and depression in prostate cancer (PCa) patients. A total of 104 men with PCa completed inventories on PR, depression, and background factors, plus gave a s le of their saliva for cortisol assay. The inverse correlation between PR and depression was present only for PCa patients with low or moderate concentrations of salivary cortisol (when classified as more than 1.0 SD below the mean vs within 1.0 SD of the group mean) but not for those men whose cortisol was >1.0 SD from the group mean. Specific PR factors and behaviours that made the greatest contribution to depression were identified for the low and moderate cortisol groups. These results suggest that there are particular aspects of PR that are most strongly related to depression, but that PR's inverse association with depression may be absent in participants with extreme chronic physiological stress.

Polymer End Group Control through a Decarboxylative Cobalt-Mediated Radical Polymerization: New Avenues for Synthesizing Peptide, Protein, and Nanomaterial Conjugates

Publisher: American Chemical Society (ACS)

Date: 30-11-2021

DOI: 10.1021/JACSAU.1C00453

Single addition of an allylamine monomer enables access to end-functionalized RAFT polymers for native chemical ligation

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C6CC06010B

Abstract: A novel method for the introduction of a single protected amine-functional monomer at the chain end of RAFT polymers has been developed to enable native chemical ligation with peptide thioesters.

Total Synthesis of Suillusin

Publisher: American Chemical Society (ACS)

Date: 31-10-2018

DOI: 10.1021/ACS.ORGLETT.8B03234

Abstract: The first total synthesis of the fungal natural product suillusin is reported. The key features of the synthesis include a Michael-benzoin multicatalytic cascade that assembles the entire carbon framework in a single step, and a Rubottom-Swern oxidation sequence that yields the requisite diketone oxidation state of the core framework. This 10-step synthesis of suillusin will allow further evaluation of the biogenesis and the biological activity of the fungal metabolite.

Comparing a genetic and a psychological factor as correlates of anxiety, depression, and chronic stress in men with prostate cancer

Publisher: Springer Science and Business Media LLC

Date: 30-03-2018

DOI: 10.1007/S00520-018-4183-4

Abstract: Some prostate cancer (PCa) patients become clinically anxious or depressed after diagnosis and treatment. Some also show the physiological signs of chronic stress. However, there are currently no data describing how these particular patients might be identified at intake. This study tested the in idual and combined predictive power of a psychological factor and a genetic factor as potential predictors of anxiety, depression, and chronic stress in a s le of PCa patients. Ninety-five PCa patients completed psychological inventories for anxiety, depression, and psychological resilience (PR) and also gave a saliva s le for cortisol and a mouthwash s le for genetic testing for the presence of the BDNF Val66Met polymorphism. High PR patients had significantly lower anxiety and depression than low PR patients, but showed no significant differences in their salivary cortisol. Carriers of the Met allele of the BDNF Val66Met polymorphism had significantly higher salivary cortisol concentrations than patients who did not carry this allele. Each of these two factors may provide valuable information regarding the vulnerability of PCa patients to anxiety, depression, or chronic stress. Suggestions are made for their inclusion in clinical settings.

Polymer Endgroup Control Through a Trifunctional Cobalt-Mediated Radical Polymerization: New Avenues for Synthesising Protein Conjugates

Publisher: American Chemical Society (ACS)

Date: 04-11-2020

DOI: 10.26434/CHEMRXIV.13185572.V1

Abstract: Cobalt-mediated radical polymerisations (CMRPs) have been initiated by the radical decarboxylation of tetrachlorophthalimide activated esters. This allows for the controlled radical polymerisation of both activated and less activated monomers across a broad temperature range with a single cobalt species, with incorporation of polymer endgroups derived from simple carboxylic acids derivatives and termination with an organozinc reagent. This method has been applied to the synthesis of a water-soluble protein olymer conjugate, demonstrating the first ex le of CMRP in protein conjugation.

Site-selective solid-phase synthesis of a CCR5 sulfopeptide library to interrogate HIV binding and entry

Publisher: American Chemical Society (ACS)

Date: 24-07-2014

DOI: 10.1021/CB500337R

Peptide ligation chemistry at selenol amino acids

Publisher: Wiley

Date: 28-11-2013

DOI: 10.1002/PSC.2581

Abstract: The convergent assembly of peptide fragments by native chemical ligation has revolutionized the way in which proteins can be accessed by chemical synthesis. A variation of native chemical ligation involves the reaction of peptides bearing an N-terminal selenocysteine residue with peptide thioesters, which proceeds through the same mechanism as the parent reaction. This transformation was first investigated in 2001 for the installation of selenocysteine into peptides and proteins via ligation chemistry. The recent discovery that selenocysteine residues within peptides can be chemoselectively deselenized without the concomitant desulfurization of cysteine residues has led to renewed interest in ligation chemistry at selenocysteine. This review outlines the use of selenocysteine in ligation chemistry as well as recent investigations of chemoselective ligation-deselenization chemistry at other selenol-derived amino acids that have the potential to greatly expand the number of targets that can be accessed by chemical synthesis.

One-Pot Ligation-Oxidative Deselenization at Selenocysteine and Selenocystine

Publisher: Wiley

Date: 14-12-2016

DOI: 10.1002/CHEM.201604709

Abstract: The use of native chemical ligation at selenocysteine (Sec) residues with peptide thioesters and additive-free selenocystine ligation with peptides bearing phenyl selenoesters, in concert with one-pot oxidative deselenization chemistry, is described. These approaches provide a simple and rapid method for accessing native peptides with serine in place of Sec at the ligation junction. The efficiency of both variants of the one-pot ligation-oxidative deselenization chemistry is probed through the synthesis of a MUC5AC-derived glycopeptide.

Development of Antiplasmodial Peptide–Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells

Publisher: American Chemical Society (ACS)

Date: 26-05-2023

DOI: 10.1021/ACS.BIOCONJCHEM.3C00147

Oxidative deselenization of selenocysteine: Applications for programmed ligation at serine

Publisher: Wiley

Date: 09-2015

DOI: 10.1002/ANIE.201504639

Abstract: Despite the unique chemical properties of selenocysteine (Sec), ligation at Sec is an under-utilized methodology for protein synthesis. We describe herein an unprecedented protocol for the conversion of Sec to serine (Ser) in a single, high-yielding step. When coupled with ligation at Sec, this transformation provides a new approach to programmed ligations at Ser residues. This new reaction is compatible with a wide range of functionality, including the presence of unprotected amino acid side chains and appended glycans. The utility of the methodology is demonstrated in the rapid synthesis of complex glycopeptide fragments of the epithelial glycoproteins MUC5AC and MUC4 and through the total synthesis of the structured, cysteine (Cys)-free protein eglin C.

Rapid Additive-Free Selenocystine–Selenoester Peptide Ligation

Publisher: American Chemical Society (ACS)

Date: 03-11-2015

DOI: 10.1021/JACS.5B07237

Abstract: We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies. Our new reaction manifold is also showcased in the total synthesis of two proteins.

Thiazolidine-Protected β-Thiol Asparagine: Applications in One-Pot Ligation–Desulfurization Chemistry

Publisher: American Chemical Society (ACS)

Date: 23-09-2015

DOI: 10.1021/ACS.ORGLETT.5B02468

Abstract: The synthesis of a β-thiol asparagine derivative bearing a novel (2,4,6-trimethoxyphenyl)thiazolidine protecting group is described. The efficient incorporation of the amino acid into the N-termini of peptides is demonstrated as well as the utility of the β-thiol asparagine moiety for rapid ligation reactions with peptide thioesters. The streamlined synthesis of native peptide products could be accomplished using a one-pot radical desulfurization of the β-thiol auxiliary following the ligation event. The utility of the amino acid is highlighted in the efficient one-pot assembly of the HIV entry inhibitor enfuvirtide.

Self-adjuvanting multicomponent cancer vaccine candidates combining per-glycosylated muc1 glycopeptides and the toll-like receptor 2 agonist pam3CysSer

Publisher: Wiley

Date: 07-01-2011

DOI: 10.1002/ANIE.201006115

Synthesis of Beta-Thiol Phenylalanine for Applications in One-Pot Ligation-Desulfurization Chemistry

Publisher: American Chemical Society (ACS)

Date: 10-04-2015

DOI: 10.1021/ACS.ORGLETT.5B00597

Abstract: The efficient synthesis of a β-thiol phenylalanine derivative is described starting from Garner's aldehyde. The utility of this amino acid in peptide ligation-desulfurization chemistry is described, including the trifluoroethanethiol (TFET)-promoted one-pot assembly of the 62 residue peptide hormone augurin.

Complex Inhibitory Mechanism of Glycomimetics with Heparanase

Publisher: American Chemical Society (ACS)

Date: 27-06-2023

DOI: 10.1021/ACS.BIOCHEM.3C00038

Neurobiological and psychological evidence of chronic stress in prostate cancer patients

Publisher: Hindawi Limited

Date: 02-03-2017

DOI: 10.1111/ECC.12671

Abstract: To measure the prevalence and severity of Generalised Anxiety Disorder (GAD), hypo- and hypercortisolaemia, and their association in a s le of prostate cancer (PCa) patients, 97 Australian PCa patients completed a background questionnaire and the GAD-7, and provided a s le of saliva collected 30-45 min after waking. The mean GAD7 score was 9.67 (SD = 3.09), and prevalence rates for current anxiety were higher than those reported for non-PCa males of a similar age. Mean salivary cortisol concentrations (30.78 nmol/L, SD = 13.97 nmol/L) were also higher than for age-comparative non-PCa men. There was a significant inverse correlation between GAD and cortisol (r = -. 209, p < .05), and four subgroups of GAD-cortisol patients were able to be identified, with evidence of both hyper- and hypocortisolaemia. These findings provide initial neurobiological evidence of the chronic and profound nature of stress experienced by PCa patients, and also suggest a possible measure that might be used to identify most at-risk PCa patients.

The use of salivary cortisol as an index of chronic stress that correlates with depression in prostate cancer patients

Publisher: Wiley

Date: 25-01-2017

DOI: 10.1002/PON.4327

The complex inhibitory mechanism of glycomimetics with human heparanase

Publisher: Cold Spring Harbor Laboratory

Date: 05-01-2023

DOI: 10.1101/2023.01.05.522817

Abstract: Heparanase (HPSE) is the only mammalian endo-β-glucuronidase known to catalyse the degradation of heparan sulfate. Dysfunction of HPSE activity has been linked to several disease states, resulting in HPSE becoming the target of numerous therapeutic programs, yet no drug has passed clinical trials to date. Pentosan polysulfate sodium (PPS) is a heterogeneous FDA-approved drug for the treatment of interstitial cystitis and a known HPSE inhibitor. However, due to its heterogeneity, characterisation of its mechanism of HPSE inhibition is challenging. Here we show that inhibition of HPSE by PPS is complex, involving multiple overlapping binding events, each influenced by factors such as oligosaccharide length and inhibitor-induced changes in protein secondary structure. The present work advances our molecular understanding of the inhibition of HPSE, which will aid the development of therapeutics for the treatment of a broad range of pathologies associated with enzyme dysfunction including cancer, inflammatory disease and viral infections.

Umpolung strategies for the functionalization of peptides and proteins

Publisher: Royal Society of Chemistry (RSC)

Date: 2022

DOI: 10.1039/D1SC06133J

Abstract: This perspective highlights the growing body of literature that leverages polarity reversal (umpolung reactivity) for the selective modification of proteinogenic functionalities and identifies opportunities for further innovation.

Synthesis of MUC1–lipopeptide chimeras

Publisher: Royal Society of Chemistry (RSC)

Date: 2010

DOI: 10.1039/C0CC01360A

Abstract: An efficient method for the convergent assembly of MUC1-lipopeptide vaccine candidates is described. Chimeras consisting of MUC1 glycopeptides (bearing multiple copies of the T(N) and T tumour-associated carbohydrate antigens) tethered to the lipopeptide immunoadjuvant Pam(3)CysSer were synthesised in high yields using a fragment-based condensation strategy.

A new species of crested pterosaur (Pterodactyloidea, Anhangueridae) from the Lower Cretaceous (upper Albian) of Richmond, North West Queensland, Australia

Publisher: Informa UK Limited

Date: 04-05-2021

DOI: 10.1080/02724634.2021.1946068

University Of Queensland

Location: Australia

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University Of New England

Location: Australia

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National Institute Of Dramatic Art

Location: Australia

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Discovery Projects - Grant ID: DP210101585

Start Date: 01-2021

End Date: 01-2024

Amount: $380,000.00

Funder: Australian Research Council

Discovery Early Career Researcher Award - Grant ID: DE180100092

Start Date: 01-2018

End Date: 2021

Amount: $418,107.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE190100160

Start Date: 2019

End Date: 12-2019

Amount: $368,994.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE220100060

Start Date: 06-2022

End Date: 06-2023

Amount: $772,676.00

Funder: Australian Research Council

ARC Centres Of Excellence - Grant ID: CE200100012

Start Date: 01-2021

End Date: 01-2028

Amount: $35,000,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP230100415

Start Date: 2023

End Date: 12-2025

Amount: $424,590.00

Funder: Australian Research Council