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Seaport Therapeutics
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Publications
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Profiling the Role of Deacylation-Reacylation in the Lymphatic Transport of a Triglyceride-Mimetic Prodrug
Pharmaceutical Research
See publicationRecent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs.
In vitro hydrolysis experiments in simulated intestinal conditions and in vivo rat lymphatic transport experiments…Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs.
In vitro hydrolysis experiments in simulated intestinal conditions and in vivo rat lymphatic transport experiments were conducted in the presence and absence of orlistat and A922500 (inhibitors of lipolysis and TG re-esterification, respectively), to evaluate the importance of 2-MPA-TG digestion and re-esterification of 2-MPA-MG (the 2-monoglyceride derivative) in promoting lymphatic transport.
2-MPA-TG was rapidly hydrolysed to 2-MPA-MG on incubation with fresh bile and pancreatic fluid (BPF), but not in simulated gastric fluid, heat-inactivated BPF or BPF + orlistat. Orlistat markedly decreased lymphatic transport and systemic exposure of 2-MPA-TG derivatives suggesting that inhibition of pancreatic lipase hindered luminal digestion and absorption of the prodrug. A922500 also significantly decreased lymphatic transport of 2-MPA-TG but redirected MPA to the portal blood, suggesting that hindered re-acylation of 2-MPA-MG resulted in intracellular degradation.
Incorporation into TG deacylation-reacylation pathways is a critical determinant of the utility of lymph directed TG-mimetic prodrugs. -
Promiscuous 2-Aminothiazoles (PrATs): a Frequent Hitting Scaffold.
J. Med. Chem.
We have identified a class of molecules, known
as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in
biophysical binding assays. This was exemplified by 4-
phenylthiazol-2-amine being identified as a hit in 14/14
screens against a diverse range of protein targets, suggesting
that this scaffold is a poor starting point for fragment-based
drug discovery. This prompted us to analyze this scaffold in
the context of an academic fragment library used for…We have identified a class of molecules, known
as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in
biophysical binding assays. This was exemplified by 4-
phenylthiazol-2-amine being identified as a hit in 14/14
screens against a diverse range of protein targets, suggesting
that this scaffold is a poor starting point for fragment-based
drug discovery. This prompted us to analyze this scaffold in
the context of an academic fragment library used for fragment-
based drug discovery (FBDD) and two larger compound libraries used for high-throughput screening (HTS). This analysis revealed that such “promiscuous 2-aminothiazoles” (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties associated with optimizing them into a lead compound makes them, in our opinion, poor scaffolds for fragment libraries.Other authors -
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Design, Synthesis, and Biological Evaluation of Tetra-substituted Thiophenes as Inhibitors of p38a MAPK
ChemistryOPEN (Wiley)
p38α mitogen-activated protein kinase (MAPK) plays a role in several cellular processes and consequently has been a therapeutic target in inflammatory diseases, cancer, and cardiovascular disease. A number of known p38α MAPK inhibitors contain vicinal 4-fluorophenyl/4-pyridyl rings connected to either a 5- or 6-membered heterocycle. In this study, a small library of substituted thiophene-based compounds bearing the vicinal 4-fluorophenyl/4-pyridyl rings was designed using computational docking…
p38α mitogen-activated protein kinase (MAPK) plays a role in several cellular processes and consequently has been a therapeutic target in inflammatory diseases, cancer, and cardiovascular disease. A number of known p38α MAPK inhibitors contain vicinal 4-fluorophenyl/4-pyridyl rings connected to either a 5- or 6-membered heterocycle. In this study, a small library of substituted thiophene-based compounds bearing the vicinal 4-fluorophenyl/4-pyridyl rings was designed using computational docking as a visualisation tool. Compounds were synthesised and evaluated in a fluorescence polarisation binding assay.
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Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA.
Angewandte Chemie (international ed. in english)
the thiol-disulfide oxidoreductase enzyme dsba catalyzes the formation of disulfide bonds in the periplasm of gram-negative bacteria. dsba substrates include proteins involved in bacterial virulence. in the absence of dsba, many of these proteins do not fold correctly, which renders the bacteria avirulent. thus dsba is a critical mediator of virulence and inhibitors may act as antivirulence agents. biophysical screening has been employed to identify fragments that bind to dsba from escherichia…
the thiol-disulfide oxidoreductase enzyme dsba catalyzes the formation of disulfide bonds in the periplasm of gram-negative bacteria. dsba substrates include proteins involved in bacterial virulence. in the absence of dsba, many of these proteins do not fold correctly, which renders the bacteria avirulent. thus dsba is a critical mediator of virulence and inhibitors may act as antivirulence agents. biophysical screening has been employed to identify fragments that bind to dsba from escherichia coli. elaboration of one of these fragments produced compounds that inhibit dsba activity in vitro. in cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of dsba. crystal structures of inhibitors bound to dsba indicate that they bind adjacent to the active site. together, the data suggest that dsba may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.
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Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide
PLOS One
AbstractApical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum has been implicated in invasion of the host erythrocyte. It interacts with malarial rhoptry neck (RON) proteins in the moving junction that forms between the host cell and the invading parasite. Agents that block this interaction inhibit invasion and may serve as promising leads for anti-malarial drug development. The invasion-inhibitory peptide R1 binds to a hydrophobic cleft on AMA1, which is an…
AbstractApical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum has been implicated in invasion of the host erythrocyte. It interacts with malarial rhoptry neck (RON) proteins in the moving junction that forms between the host cell and the invading parasite. Agents that block this interaction inhibit invasion and may serve as promising leads for anti-malarial drug development. The invasion-inhibitory peptide R1 binds to a hydrophobic cleft on AMA1, which is an attractive target site for small molecules that block parasite invasion. In this work, truncation and mutational analyses show that Phe5-Phe9, Phe12 and Arg15 in R1 are the most important residues for high affinity binding to AMA1. These residues interact with two well-defined binding hot spots on AMA1. Computational solvent mapping reveals that one of these hot spots is suitable for small molecule targeting. We also confirm that R1 in solution binds to AMA1 with 1:1 stoichiometry and adopts a secondary structure consistent with the major form of R1 observed in the crystal structure of the complex. Our results provide a basis for designing high affinity inhibitors of the AMA1-RON2 interaction.
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Organizations
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American Chemical Society
Member
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Royal Australian Chemical Society
Member
- Present -
Royal Society of Chemistry
Member
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