Publications by authors named "David I Rhodes"

21 Publications

  • Page 1 of 1

Nerve guidance conduit development for primary treatment of peripheral nerve transection injuries: A commercial perspective.

Acta Biomater 2021 11 4;135:64-86. Epub 2021 Sep 4.

Department of Materials Science and Engineering, Monash University, 22 Alliance Lane, Clayton, Victoria 3800, Australia; School of Engineering, University of Warwick, Coventry CV4 7AL, United Kingdom. Electronic address:

Commercial nerve guidance conduits (NGCs) for repair of peripheral nerve discontinuities are of little use in gaps larger than 30 mm, and for smaller gaps they often fail to compete with the autografts that they are designed to replace. While recent research to develop new technologies for use in NGCs has produced many advanced designs with seemingly positive functional outcomes in animal models, these advances have not been translated into viable clinical products. While there have been many detailed reviews of the technologies available for creating NGCs, none of these have focussed on the requirements of the commercialisation process which are vital to ensure the translation of a technology from bench to clinic. Consideration of the factors essential for commercial viability, including regulatory clearance, reimbursement processes, manufacturability and scale up, and quality management early in the design process is vital in giving new technologies the best chance at achieving real-world impact. Here we have attempted to summarise the major components to consider during the development of emerging NGC technologies as a guide for those looking to develop new technology in this domain. We also examine a selection of the latest academic developments from the viewpoint of clinical translation, and discuss areas where we believe further work would be most likely to bring new NGC technologies to the clinic. STATEMENT OF SIGNIFICANCE: NGCs for peripheral nerve repairs represent an adaptable foundation with potential to incorporate modifications to improve nerve regeneration outcomes. In this review we outline the regulatory processes that functionally distinct NGCs may need to address and explore new modifications and the complications that may need to be addressed during the translation process from bench to clinic.
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http://dx.doi.org/10.1016/j.actbio.2021.08.052DOI Listing
November 2021

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction.

Org Biomol Chem 2016 Jul 26;14(25):6010-23. Epub 2016 May 26.

School of Chemistry, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia.

From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3'-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.
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http://dx.doi.org/10.1039/c6ob00950fDOI Listing
July 2016

Bioactive glycosides from the African medicinal plant Boerhavia erecta L.

Nat Prod Res 2015 20;29(20):1954-8. Epub 2015 Feb 20.

a School of Chemistry, University of Wollongong , Northfields Avenue, Wollongong , New South Wales 2522 , Australia.

Phytochemical studies of the previously unexplored stem of Boerhavia erecta from Burkina Faso, resulted in the isolation of an unreported glycoside 4, 2,3-dihydroxypropylbenzoate-3-O-β-[4″-methoxy] glucuronide as well as seven known glycosides (1-3, 5-8). The major isolate 5 and 8 indicated a significant inhibition against HIV integrase (IC50 10 and 22 μg/mL, respectively). The extracts and isolates were also tested for anti-malarial activity, but insignificant activity was observed.
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http://dx.doi.org/10.1080/14786419.2015.1013470DOI Listing
December 2015

Evaluation of an established pericardium patch for delivery of mesenchymal stem cells to cardiac tissue.

J Biomed Mater Res A 2015 Jun 30;103(6):1999-2005. Epub 2014 Sep 30.

CSIRO Manufacturing Flagship, Clayton, 3169, Australia.

The present study has evaluated a commercial pericardial material for its capacity to assist as a natural extracellular matrix (ECM) patch for the delivery and retention of mesenchymal stem cells for cardiac repair. The repair of cardiac tissue with cells delivered by an appropriate bioscaffold is expected to offer a superior, long-lasting treatment strategy. The present material, CardioCel®, is based on acellular pericardium that has been stabilized by treatments, including a low concentration of glutaraldehyde, that eliminate calcification after implantation. In the present study, we have assessed this material using human bone marrow mesenchymal stem cells at various cell densities under standard, static cell culture conditions. The initial seeding densities were monitored to evaluate the extent of cell attachment and cell viability, with subsequent cell proliferation assessed up to 4 weeks using an MTS assay. Cell morphology, infiltration, and spreading were tracked using scanning electron microscopy and phalloidin staining. The efficacy of long-term cell survival was further assessed by examining the extent and type of new tissue formation on seeded scaffolds at 70 days; both type I and type III collagens were present in fibrillar structures on these scaffolds indicating that the seeded stem cells had the capacity to differentiate into collagen-producing cells necessary to repair damaged ECM. These data show that the CardioCel® scaffold is an appropriate substrate for the stem cells and has the potential to both retain seeded stem cells and to act as a template for cell propagation and new tissue formation.
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http://dx.doi.org/10.1002/jbm.a.35335DOI Listing
June 2015

Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification?

J Biomol Screen 2013 Feb 8;18(2):147-59. Epub 2012 Nov 8.

St. Vincent's Institute, Fitzroy, Victoria, Australia.

Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed a fragment screening campaign on the HIV-1 integrase core domain (IN) using similar commercially purchased fragment libraries. The two campaigns used different screening methods for the preliminary identification of fragment hits; one used saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), and the other used surface plasmon resonance (SPR) spectroscopy. Both initial screens were followed by X-ray crystallography. Using the STD-NMR/X-ray approach, 15 IN/fragment complexes were identified, whereas the SPR/X-ray approach found 6 complexes. In this article, we compare the approaches that were taken by each group and the results obtained, and we look at what factors could potentially influence the final results. We find that despite using different approaches with little overlap of initial hits, both approaches identified binding sites on IN that provided a basis for fragment-based lead discovery and further lead development. Comparison of hits identified in the two studies highlights a key role for both the conditions under which fragment binding is measured and the criteria selected to classify hits.
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http://dx.doi.org/10.1177/1087057112465979DOI Listing
February 2013

Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C-terminal amino acid variations.

Beilstein J Org Chem 2012 9;8:1265-70. Epub 2012 Aug 9.

School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.

The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2-4 μg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.
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http://dx.doi.org/10.3762/bjoc.8.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458747PMC
October 2012

Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

PLoS One 2012 10;7(7):e40147. Epub 2012 Jul 10.

CSIRO Materials, Science and Engineering, Parkville, Victoria, Australia.

A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393750PMC
March 2013

Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site.

Chembiochem 2011 Oct 17;12(15):2311-5. Epub 2011 Aug 17.

Avexa Ltd, 576 Swan Street, Melbourne 3121, Australia.

An optimised method of solution cyclisation gave us access to a series of peptides including SLKIDNLD (2). We investigated the crystallographic complexes of the HIV integrase (HIV-IN) catalytic core domain with 13 of the peptides and identified multiple interactions at the binding site, including hydrogen bonds with residues Thr125 and Gln95, that have not previously been described as being accessible within the binding site. We show that the peptides inhibit the interaction of lens epithelium-derived growth factor (LEDGF) with HIV-IN in a proximity AlphaScreen assay and in an assay for the LEDGF enhancement of HIV-IN strand transfer. The interactions identified represent a potential framework for the development of new HIV-IN inhibitors.
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http://dx.doi.org/10.1002/cbic.201100350DOI Listing
October 2011

Synthesis and antibacterial activity of C2-symmetric binaphthyl scaffolded amino acid derivatives.

Eur J Med Chem 2011 Sep 25;46(9):4201-11. Epub 2011 Jun 25.

School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.

The synthesis of eleven novel antibacterial agents is reported. The structures are based on a C(2)-symmetric binaphthyl scaffold which holds two identical chains consisting of a short linker, a basic amino acid and a small hydrophobic side chain. Antibacterial activity is revealed for a number of derivatives down to an MIC of 2 μg/mL (2 μM) against Staphylococcus aureus--comparable to vancomycin, and an MIC of 31 μg/mL (31 μM) against some vancomycin-resistant enterococcal strains.
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http://dx.doi.org/10.1016/j.ejmech.2011.06.024DOI Listing
September 2011

Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design.

Antivir Chem Chemother 2011 Mar 7;21(4):155-68. Epub 2011 Mar 7.

Avexa Ltd, Richmond, Australia.

Background: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations.

Methods: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands.

Results: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors.

Conclusions: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold.
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http://dx.doi.org/10.3851/IMP1716DOI Listing
March 2011

Synthesis and antibacterial activity of some binaphthyl-supported macrocycles containing a cationic amino acid.

Bioorg Med Chem 2011 Jun 14;19(11):3549-57. Epub 2011 Apr 14.

School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.

As part of a programme investigating antibacterial cyclic macrocycles containing a cationic amino acid with an internal aromatic hydrophobic scaffold, we previously reported a macrocycle anchored at the 3,3'-positions of a 1,1'-binaphthyl unit. This was prepared via key intermediates containing an internal allylglycine and an allyl-substituted binaphthyl unit for a subsequent ring-closing metathesis reaction. This paper presents some structure-activity relationship studies with additional macrocycles based on this lead compound against Staphylococcus aureus together with the antibacterial activity of two related acyclic compounds.
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http://dx.doi.org/10.1016/j.bmc.2011.04.013DOI Listing
June 2011

Fragment-based design of ligands targeting a novel site on the integrase enzyme of human immunodeficiency virus 1.

ChemMedChem 2011 Feb 16;6(2):258-61. Epub 2010 Dec 16.

Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Australia.

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http://dx.doi.org/10.1002/cmdc.201000483DOI Listing
February 2011

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 2: azoles: effective metal chelators.

Bioorg Med Chem Lett 2010 Oct 27;20(19):5909-12. Epub 2010 Jul 27.

Avexa Ltd, 576 Swan Street, Richmond, Victoria 3121, Australia.

Synthesis of a diverse set of azoles and their utilizations as an amide isostere in the design of HIV integrase inhibitors is described. The Letter identified thiazole, oxazole, and imidazole as the most promising heterocycles. Initial SAR studies indicated that these novel series of integrase inhibitors are amenable to lead optimization. Several compounds with low nanomolar inhibitory potency are reported.
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http://dx.doi.org/10.1016/j.bmcl.2010.07.081DOI Listing
October 2010

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: selection of the scaffold.

Bioorg Med Chem Lett 2010 Oct 27;20(19):5913-7. Epub 2010 Jul 27.

Avexa Ltd, 576 Swan Street, Richmond, Victoria 3121, Australia.

HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC(50) of 3 nM against wild type HIV infected T-cells.
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http://dx.doi.org/10.1016/j.bmcl.2010.07.079DOI Listing
October 2010

Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses.

Bioorg Med Chem Lett 2010 Sep 16;20(17):5013-8. Epub 2010 Jul 16.

Avexa Ltd, 576 Swan Street, Richmond, Victoria 3121, Australia.

A series of novel HIV integrase inhibitors active against rategravir resistant strains are reported. Initial SAR studies revealed that activities against wild-type virus were successfully maintained at single digit nanomolar level with a wide range of substitutions. However, inclusion of nitrogen-based cyclic substitutions was crucial for achieving potency against mutant viruses. Several compounds with excellent activities against wild-type virus as well as against the viruses with the mutations Q148H/G140S or N155H/E92Q were reported.
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http://dx.doi.org/10.1016/j.bmcl.2010.07.041DOI Listing
September 2010

Synthesis and antibacterial studies of binaphthyl-based tripeptoids. Part 2.

Bioorg Med Chem 2010 Jul 2;18(13):4793-800. Epub 2010 Jun 2.

School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.

A compact synthesis of 15 new binaphthyl-based dicationic tripeptoids and one biphenyl based dicationic tripeptoid is described. Fourteen of these tripeptoids resulted from variation of the C-2' ether substituent of the binaphthyl unit. An O-iso-butyl ether binaphthyl derivative was found to be the most active against Staphylococcus aureus (MIC 1.95 μg/mL). The biphenyl analogue also showed good activity against S. aureus (MIC 1.95 μg/mL). These compounds, however, were less active against four vancomycin-resistant strains of enterococci (VRE) than some of our previously developed compounds that had an O-iso-pentyl ether substituent on the binaphthyl unit and a C-2 L-Leu moiety.
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http://dx.doi.org/10.1016/j.bmc.2010.05.005DOI Listing
July 2010

Synthesis and antibacterial studies of binaphthyl-based tripeptoids. Part 1.

Bioorg Med Chem 2010 Apr 23;18(7):2611-20. Epub 2010 Feb 23.

School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.

An efficient synthesis of 29 new binaphthyl-based neutral, and mono- and di-cationic, peptoids is described. Some of these compounds had antibacterial activities with MIC values of 1.9-3.9microg/mL against Staphylococcus aureus. One peptoid had a MIC value of 6microg/mL against a methicillin-resistant strain of S. aureus (MRSA) and a MIC value of 2microg/mL against vancomycin-resistant strains of enterococci (VRE).
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http://dx.doi.org/10.1016/j.bmc.2010.02.033DOI Listing
April 2010

Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site.

FEBS Lett 2010 Apr 16;584(8):1455-62. Epub 2010 Mar 16.

Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.

HIV integrase (IN) is an essential enzyme in HIV replication and an important target for drug design. IN has been shown to interact with a number of cellular and viral proteins during the integration process. Disruption of these important interactions could provide a mechanism for allosteric inhibition of IN. We present the highest resolution crystal structure of the IN core domain to date. We also present a crystal structure of the IN core domain in complex with sucrose which is bound at the dimer interface in a region that has previously been reported to bind integrase inhibitors.
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http://dx.doi.org/10.1016/j.febslet.2010.03.016DOI Listing
April 2010

Binaphthyl scaffolded peptoids via ring-closing metathesis reactions and their anti-bacterial activities.

Bioorg Med Chem Lett 2009 Jun 18;19(11):3010-3. Epub 2009 Apr 18.

School of Chemistry, University of Wollongong, Wollongong, NSW, Australia.

An efficient synthesis of four new acyclic and four new cyclic binaphthyl-based cationic peptoids is described. These compounds had anti-bacterial activities with MIC values of 4-62 microg/mL against Staphylococcus aureus.
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http://dx.doi.org/10.1016/j.bmcl.2009.04.046DOI Listing
June 2009

Longitudinal analysis of human immunodeficiency virus type 1 nef/long terminal repeat sequences in a cohort of long-term survivors infected from a single source.

J Virol 2006 Jan;80(2):1047-52

Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne 3001, Victoria, Australia.

We studied the evolution of human immunodeficiency virus type 1 (HIV-1) in a cohort of long-term survivors infected with an attenuated strain of HIV-1 acquired from a single source. Although the cohort members experienced differing clinical courses, we demonstrate similar evolution of HIV-1 nef/long-terminal repeat (LTR) sequences, characterized by progressive sequence deletions tending toward a minimal nef/LTR structure that retains only sequence elements required for viral replication. The in vivo pathogenicity of attenuated HIV-1 is therefore dictated by viral and/or host factors other than those that impose a unidirectional selection pressure on the nef/LTR region of the HIV-1 genome.
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http://dx.doi.org/10.1128/JVI.80.2.1047-1052.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1346882PMC
January 2006
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