ORCID Profile
0000-0002-0341-065X
Current Organisation
The University of Auckland
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Publisher: American Chemical Society (ACS)
Date: 16-01-2018
DOI: 10.1021/ACS.ORGLETT.7B03925
Abstract: The first total synthesis of the highly N-methylated acetylene-containing lipopeptide jahanyne, an apoptosis-inducing natural product from marine cyanobacteria, is reported. A late-stage solution-phase coupling enabled introduction of the C-terminal ketone pyrrolidine moiety. A modified Fmoc solid-phase synthesis strategy was adopted to effectively couple multiple sterically hindered N-methylated amino acids while suppressing epimerization. The total synthesis has enabled confirmation of the proposed absolute configuration of natural jahanyne.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2021
DOI: 10.2174/0929867327666201006153847
Abstract: Prostate cancer is one of the most common cancers worldwide, with approximately 1.1 million cases diagnosed annually. The rapid development of molecular imaging has facilitated greater structural understanding which can help formulate novel combination therapeutic regimens and more accurate diagnosis avoiding unnecessary prostate biopsies. This accumulated knowledge also provides greater understanding into aggressive stages of the disease and tumour recurrence. Recently, much progress has been made on developing peptidomimetic-based inhibitors as promising candidates to effectively bind to the prostate-specific membrane antigen (PSMA) which is expressed by prostate cancer cells. In this review, recent advances covering small-molecule and peptide-based PSMA inhibitors will be extensively reviewed, providing a base for the rational design of future PSMA inhibitors. Herein, the literature on selected PSMA inhibitors that have been developed from 1996 to 2020 were reviewed, emphasizing recent synthetic advances and chemical strategies whilst highlighting therapeutic potential and drawbacks of each inhibitor. Synthesized inhibitors presented in this review demonstrate the clinical application of certain PSMA inhibitors, exhibited in vitro and in vivo. This review highlights the clinical potential of PSMA inhibitors, analyzing the advantages and setbacks of the chemical synthetic methodologies utilized, setting precedence for the discovery of novel PSMA inhibitors for future clinical applications.
Publisher: American Chemical Society (ACS)
Date: 26-02-2020
Publisher: Wiley
Date: 15-10-2021
DOI: 10.1111/BPH.15628
Abstract: The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR‐like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans. To facilitate understanding of translational and preclinical data, we need to know the receptor pharmacology of this family in mice. Plasmids encoding mouse CLR/CTR and RAMPs were transiently transfected into Cos‐7 cells. cAMP production was measured in response to agonists in the absence or presence of antagonists. We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and βCGRP and of mouse CTR without or with mouse RAMPs. Receptors containing m‐CTR had subtly different pharmacology than human receptors they were promiscuous in their pharmacology, both with and without RAMPs. Several peptides, including mouse αCGRP and mouse adrenomedullin 2, were potent agonists of the m‐CTR:m‐RAMP3 complex. Pharmacological profiles of receptors comprising m‐CLR:m‐RAMPs were generally similar to those of their human counterparts, albeit with reduced specificity. Mouse receptor pharmacology differed from that in humans, with mouse receptors displaying reduced discrimination between ligands. This creates challenges for interpreting which receptor may underlie an effect in preclinical models and thus translation of findings from mice to humans. It also highlights the need for new ligands to differentiate between these complexes. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary).. To view the other articles in this section visit oi/10.1111/bph.v179.3/issuetoc
Publisher: American Chemical Society (ACS)
Date: 08-12-2022
Publisher: Wiley
Date: 25-11-2016
Publisher: MDPI AG
Date: 09-11-2022
Abstract: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy in iduals and migraine-like attacks in patients however, it is not clear whether targeting this system could be therapeutically efficacious. To effectively target the PACAP system, an understanding of PACAP receptor distribution is required. Therefore, this study aimed to characterize commercially available antibodies and use these to detect PACAP-responsive receptors in the TG. Antibodies were initially validated in receptor transfected cell models and then used to explore receptor expression in rat and human TG. Antibodies were identified that could detect PACAP-responsive receptors, including the first antibody to differentiate between the PAC1n and PAC1s receptor splice variants. PAC1, VPAC1, and VPAC2 receptor-like immunoreactivity were observed in subpopulations of both neuronal and glial-like cells in the TG. In this study, PAC1, VPAC1, and VPAC2 receptors were detected in the TG, suggesting they are all potential targets to treat migraine. These antibodies may be useful tools to help elucidate PACAP-responsive receptor expression in tissues. However, most antibodies exhibited limitations, requiring the use of multiple methodologies and the careful inclusion of controls.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2NJ01016J
Abstract: Intramolecular ring-closing metathesis on an N , N -diallyl Glu-urea-Gly substrate affords 7-membered cyclic ureas as inhibitors of prostrate specific membrane antigen (PMSA).
Publisher: American Chemical Society (ACS)
Date: 22-11-2022
DOI: 10.1021/ACSINFECDIS.1C00347
Abstract: With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity issues. Using thiol-ene chemistry, the facile preparation of six unique S-lipidated building blocks was demonstrated and used to generate lipopeptide mimetics upon incorporation into solid-phase peptide synthesis (SPPS). We then designed and synthesized 38 polymyxin analogues, incorporating these unique building blocks at the N-terminus, or to replace hydrophobic residues at positions 6 and 7 of the native lipopeptides. Several polymyxin analogues bearing one or more S
Publisher: American Chemical Society (ACS)
Date: 07-02-2018
DOI: 10.1021/ACS.BIOCHEM.7B01180
Abstract: The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands. These two domains are joined together by a stretch of amino acids that is referred to as the "stalk". Studies of other class B GPCRs suggest that the stalk may act as hinge, allowing the ECD to adopt multiple conformations. It is unclear what the role of the stalk is within CLR and whether RAMPs can influence its function. Therefore, this study investigated the role of this region using an alanine scan. Effects of mutations were measured with all three RAMPs through cell surface expression, cAMP production and, in select cases, radioligand binding and total cell expression assays. Most mutants did not affect expression or cAMP signaling. CLR C127A, N140A, F142A, and L144A impaired cell surface expression with all three RAMPs. T125A decreased the potency of all peptides at all receptors. N128A, V135A, and L139A showed ligand-dependent effects. While the stalk appears to play a role in CLR function, the effect of RAMPs on this region seems limited, in contrast to their effects on the structure of CLR in other receptor regions.
Publisher: Wiley
Date: 31-10-2021
DOI: 10.1111/BPH.15700
Abstract: The pituitary adenylate cyclase‐activating peptide (PACAP) family is of clinical interest for the treatment of migraine. These peptides activate three different PACAP‐responsive class B G protein‐coupled receptors: the PAC 1 , VPAC 1 and VPAC 2 receptors. The PAC 1 receptor may be alternatively spliced, generating variants that can differ in their pharmacological or signalling profiles. To inform drug discovery efforts targeting migraine, we need to better understand how the different PACAP‐responsive receptors signal and how effectively these responses can be blocked by antagonists. The signalling profiles of the human PAC 1n , PAC 1s , VPAC 1 and VPAC 2 receptors were examined in transfected Cos7 cells for cAMP, IP 1 , pAkt, pERK and pCREB. Biased signalling was then quantified. The ability of antagonists to block PACAP‐38, PACAP‐27 or VIP stimulated cAMP accumulation at PACAP‐responsive receptors was also determined. PACAP‐responsive receptors exhibited varied pharmacological profiles but activated signalling in a similar manner. The PAC 1n and PAC 1s receptors displayed distinct pharmacology. At the PAC 1s receptor, VIP and PHM were more potent than at the PAC 1n receptor. PACAP‐responsive receptors displayed agonist‐dependent antagonism where PACAP‐38 was less effectively antagonised compared to PACAP‐27 and VIP. The distinct pharmacological profile displayed by the PAC 1s receptor suggests that it can act as a dual receptor for VIP and PACAP. Furthermore, the effectiveness of blocking a signalling pathway can be influenced by which endogenous PACAP family agonist is present. These effects have potential implications for the development and effectiveness of drugs targeting the PACAP system. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit oi/10.1111/bph.v179.3/issuetoc
Publisher: American Chemical Society (ACS)
Date: 26-02-2020
No related grants have been discovered for Andrew Siow.