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Featured researches published by A. K. Wong.


Current Medicinal Chemistry | 2001

Lipid, Sugar and Liposaccharide Based Delivery Systems

A. K. Wong; Istvan Toth

Although there are formidable barriers to the oral delivery of biologically active drugs, considerable progress in the field has been made, using both physical and chemical strategies of absorption enhancement. A possible method to enhance oral absorption is to exploit the phenomenon of lipophilic modification and mono and oligosaccharide conjugation. Depending on the uptake mechanism targeted, different modifications can be employed. To target passive diffusion, lipid modification has been used, whereas the targeting of sugar transport systems has been achieved through drugs conjugated with sugars. These drug delivery units can be specifically tailored to transport a wide variety of poorly absorbed drugs through the skin, and across the barriers that normally inhibit absorption from the gut or into the brain. The delivery system can be conjugated to the drug in such a way as to release the active compound after it has been absorbed (i.e. the drug becomes a prodrug), or to form a biologically stable and active molecule (i.e. the conjugate becomes a new drug moiety). Examples where lipid, sugar and lipid-sugar conjugates have resulted in enhanced drug delivery will be highlighted in this review.


British Journal of Pharmacology | 1999

Pharmacological characterization of antagonists of the C5a receptor

Natalii J Paczkowski; Angela M. Finch; Jacqueline B Whitmore; Anna Short; A. K. Wong; Peter N. Monk; Stuart A. Cain; David P. Fairlie; Stephen M. Taylor

Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). In this study we compared a new cyclic antagonist, F‐[OPdChaWR], with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a. In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. There were differences in selectivities for the C5aR with F‐[OPdChaWR] (pKb 8.64±0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16±0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19±0.38 vs pKb 8.28±0.29, respectively) in umbilical artery. This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (−logIC50 values) for C5aR in umbilical artery membranes (F‐[OPdChaWR], 7.00±0.46; MeFKPdChaWr, 7.23±0.17), whereas in PMN membranes the C5aR affinity of the cycle F‐[OPdChaWR] (7.05±0.06) was four times higher than that of acyclic MeFKPdChaWr (6.43±0.24, P<0.05). In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. The nature of these differences is yet to be elucidated.


British Journal of Pharmacology | 1999

Effects of a new C5a receptor antagonist on C5a- and endotoxin-induced neutropenia in the rat.

Anna Short; A. K. Wong; Angela M. Finch; Gerald Haaima; Ian A. Shiels; David P. Fairlie; Stephen M. Taylor

A new C5a receptor antagonist, the cyclic peptide Phe‐[Orn‐Pro‐D‐cyclohexylalanine‐Trp‐Arg], (F‐[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinant C5a (2 μg kg−1 i.v.) caused rapid neutropenia, characterized by an 83% decrease in circulating polymorphonuclear leukocytes (PMNs) at 5 min. Administration of F‐[OPdChaWR] (0.3–3 mg kg−1 i.v.), did not affect the levels of circulating PMNs but, when given 10 min prior to C5a, it inhibited the C5a‐induced neutropenia by up to 70%. Administration of E. Coli lipopolysaccharide (LPS, 1 mg kg−1 i.v.) also caused neutropenia with an 88% decrease in circulating PMNs after 30 min. When rats were pretreated with F‐[OPdChaWR] (0.3–10 mg kg−1 i.v.) 10 min prior to LPS, there was a dose‐dependent antagonism of the neutropenia caused by LPS, with up to 69% reversal of neutropenia observed 30 min after LPS administration. These findings suggest that C5a receptor antagonists may have therapeutic potential in the many diseases known to involve either endotoxin or C5a.


Inflammation | 2001

Species dependence for binding of small molecule agonist and antagonists to the C5a receptor on polymorphonuclear leukocytes.

Trent M. Woodruff; Anna J. Strachan; Sam D. Sanderson; Peter N. Monk; A. K. Wong; David P. Fairlie; Stephen M. Taylor

This study investigated the receptor binding affinities of a C5a agonist and cyclic antagonists for polymorphonuclear leukocytes (PMNs) isolated from human, sheep, pig, dog, rabbit, guinea pig, rat and mouse. The affinities of the two small molecule antagonists, F-[OPdChaWR] and AcF-[OPdChaWR], and the agonist, YSFKPMPLaR, revealed large differences in C5a receptor (C5aR) affinities between species. The antagonists bound to human, rat and dog PMNs with similar high affinities, but with lower affinities to PMNs from all other species. The C5a agonist also bound with varying affinities between species, but showed a different affinity profile to the antagonists. In contrast, recombinant human C5a had similar affinity for PMNs of all species investigated. The low correlation between the affinities of the antagonists and the agonist between species either suggests that different receptor residues are important for distinguishing between agonist/antagonist binding, or that the agonist and antagonist peptides bind to two distinct sites within the C5aR.


Infection and Immunity | 2002

A lipid core peptide construct containing a conserved region determinant of the group A streptococcal M protein elicits heterologous opsonic antibodies.

Colleen Olive; Michael R. Batzloff; Aniko Horvath; A. K. Wong; Timothy Clair; Penny Yarwood; Istvan Toth; Michael F. Good

ABSTRACT The study reported here investigated the immunogenicity and protective potential of a lipid core peptide (LCP) construct containing a conserved region determinant of M protein, defined as peptide J8. Parenteral immunization of mice with LCP-J8 led to the induction of high-titer serum immunoglobulin G J8-specific antibodies when the construct was coadministered with complete Freunds adjuvant (CFA) or administered alone. LCP-J8 in CFA had significantly enhanced immunogenicity compared with the monomeric peptide J8 given in CFA. Moreover, LCP-J8/CFA and LCP-J8 antisera opsonized four different group A streptococcal (GAS) strains, and the antisera did not cross-react with human heart tissue proteins. These data indicate the potential of an LCP-based M protein conserved region GAS vaccine in the induction of broadly protective immune responses in the absence of a conventional adjuvant.


European Journal of Pharmaceutical Sciences | 2002

Determination of transport in the Caco-2 cell assay of compounds varying in lipophilicity using LC–MS: enhanced transport of Leu-enkephalin analogues

A. K. Wong; Benjamin P. Ross; Y. Chan; Per Artursson; Lucia Lazorova; Alun Jones; Istvan Toth

PURPOSE To synthesize a number of analogues of Leu-enkephalin with different lipophilicities and to develop an LC-MS method for determining the Caco-2 cell permeability values of these compounds. METHODS A number of sugar and sugar plus lipoamino acid analogues of Leu-enkephalin were synthesized by solid-phase and solution methods. An LC-MS method was developed for analyzing the Caco-2 cell assay samples and validated against the traditional method using radiolabelled compounds. RESULTS A sensitive and specific LC-MS assay was developed. Standard curves were linear in the range of 0.025-5 microM. Apparent permeability values determined by LC-MS and liquid scintillation counter were identical, for both a hydrophilic drug, cephalexin and a lipophilic Leu-enkaphalin analogue. Caco-2 permeability values for the analogues of Leu-enkephalin were determined and it was found that attachment of sugar or sugar and lipoamino acid to the Leu-enkephalin peptide resulted in an increase in the apparent permeability values compared to the native peptide, which was not transported across the Caco-2 cell monolayers. CONCLUSIONS A rapid, generic LC-MS method for analyzing a range of compounds was developed. Attachment of a sugar or sugar and lipoamino acid to Leu-enkephalin improves the apparent permeability across Caco-2 cell monolayers.


Letters in Peptide Science | 2001

A lipophilic adjuvant carrier system for antigenic peptides

Aniko Horvath; Colleen Olive; A. K. Wong; Timothy Clair; Penny Yarwood; Michael F. Good; Istvan Toth

A lipoamino acid based synthetic peptide, (Lipid Core Peptide, LCP) derived from the conserved region of group A streptococci (GAS) was evaluated as potential candidate in a vaccine to prevent GAS-associated diseases, including rheumatic heart disease and post-streptococcal acute glomerulonephritis. Multiple copies of a peptide sequence from the bacterial surface M protein were incorporated into a lipid core and it was used to immunize mice with and without the application of adjuvant. The LCP construct had significantly enhanced immunogenicity compared with the monomeric peptide epitope. Furthermore, the peptides incorporated into the LCP system generated antibodies without the use of any conventional adjuvant.


2nd International Peptide Symposium & 17th American Peptide Symposium | 2001

Lipoamino Acid and Liposaccharide Conjugated Peptides: Enhancement of Bioavailability

Y. Chan; A. K. Wong; Istvan Toth

The most convenient way to administer drugs is by oral administration. However, intestinal absorption of peptides/proteins is relatively poor, mainly due to extensive enzymatic degradation in the gastrointestinal tract. The aim of the present study was to improve the intestinal absorption and stability of a model peptide IT-100 by chemically conjugating it with a lipid and sugar based carrier system. Lipoamino acids enhance the membrane permeability and metabolic stability of peptides, and have been investigated extensively in drug delivery [1]. However, lipoamino acid conjugation can considerably reduce water solubility. Further sugar conjugation not only improves the physico-chemical properties of the lipophilic compounds (water solubility), but also may allow utilisation of active transport uptake systems such as the Na+ dependent D-glucose transporter [2].


Journal of Medicinal Chemistry | 1999

Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a.

Angela M. Finch; A. K. Wong; Natalii J Paczkowski; Wadi Sk; David J. Craik; David P. Fairlie; Stephen M. Taylor


Journal of Medicinal Chemistry | 2000

Conformational selection of inhibitors and substrates by proteolytic enzymes: Implications for drug design and polypeptide processing

David P. Fairlie; Joel D. A. Tyndall; Robert C. Reid; A. K. Wong; Giovanni Abbenante; Martin J. Scanlon; Darren R. March; Douglas A. Bergman; Christina L. L. Chai; Brendan A. Burkett

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Istvan Toth

University of Queensland

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Angela M. Finch

University of New South Wales

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Colleen Olive

QIMR Berghofer Medical Research Institute

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Y. Chan

University of Queensland

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Penny Yarwood

QIMR Berghofer Medical Research Institute

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Timothy Clair

QIMR Berghofer Medical Research Institute

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