Joel Tyndall - Academia.edu (original) (raw)

Papers by Joel Tyndall

Recent Patents on Anti-Cancer Drug Discovery, 2021

Background: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxici... more Background: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. The key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety. Objective: Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells. Methods: In this review, an integrated view of the potential use of prodrugs and ADCs in cancer ...

SDS-PAGE gels of full length β-casein cleavage by wild type CtHtrA and mutants over a 60 min time... more SDS-PAGE gels of full length β-casein cleavage by wild type CtHtrA and mutants over a 60 min time course. A. Wild-type CtHtrA; B. CtHtrAA240V; C. CtHtrAE47K; D. CtHtrAG268R; E. CtHtrAG475E; F. CtHtrAP370L; G. CtHtrAR55Q. Lanes are labelled: M: protein molecular weight marker (Bio-Rad); 0 min; 10 min; 20 min; 30 min; 40 min; 50 min; 60 min; H: CtHtrA only; βc: β-casein only. The molecular masses of standard proteins are indicated by arrows next to the gels. (DOC 21 kb)

EMS library mutants with confirmed non-synonymous SNVs in the cthtrA gene. Table S2. List of bact... more EMS library mutants with confirmed non-synonymous SNVs in the cthtrA gene. Table S2. List of bacterial strains used in this study. Table S3. Total SNVs present in the cthtrA A240V, cthtrA P370L, and cthtrA G475E mutants as confirmed by whole genome sequencing. Table S4. Sequences and associated annealing temperatures for the PCR primers used in this study. Table S5. Active site substrates and activators used for proteolysis and oligomerisation assays. (DOCX 45 kb)

Infections by fungal pathogens such as Candida albicans and Aspergillus fumigatus and their resis... more Infections by fungal pathogens such as Candida albicans and Aspergillus fumigatus and their resistance to triazole drugs are major concerns. Fungal lanosterol 14-demethylase belongs to the CYP51 class in the cytochrome P450 superfamily of enzymes. This monospanning bitopic membrane protein is involved in ergosterol biosynthesis and is the primary target of azole antifun-gal drugs, including fluconazole. The lack of high-resolution structural information for this drug target from fungal pathogens has been a limiting factor for the design of modified triazole drugs that will overcome resistance. Here we report the X-ray struc-ture of full-length Saccharomyces cerevisiae lanosterol 14-demethylase in complex with fluconazole at a resolution of 2.05 Å. This structure shows the key interactions involved in fluconazole binding and provides insight into resistance mechanisms by revealing a water-mediated hydrogen bonding network between the drug and tyrosine 140, a residue frequently foundm...

PloS one, 2016

Azole antifungals, known as demethylase inhibitors (DMIs), target sterol 14α-demethylase (CYP51) ... more Azole antifungals, known as demethylase inhibitors (DMIs), target sterol 14α-demethylase (CYP51) in the ergosterol biosynthetic pathway of fungal pathogens of both plants and humans. DMIs remain the treatment of choice in crop protection against a wide range of fungal phytopathogens that have the potential to reduce crop yields and threaten food security. We used a yeast membrane protein expression system to overexpress recombinant hexahistidine-tagged S. cerevisiae lanosterol 14α-demethylase and the Y140F or Y140H mutants of this enzyme as surrogates in order characterize interactions with DMIs. The whole-cell antifungal activity (MIC50 values) of both the R- and S-enantiomers of tebuconazole, prothioconazole (PTZ), prothioconazole-desthio, and oxo-prothioconazole (oxo-PTZ) as well as for fluquinconazole, prochloraz and a racemic mixture of difenoconazole were determined. In vitro binding studies with the affinity purified enzyme were used to show tight type II binding to the yeast...

Pharmaceutics

Nanoparticle drug delivery systems have emerged as a promising strategy for overcoming limitation... more Nanoparticle drug delivery systems have emerged as a promising strategy for overcoming limitations of antimicrobial drugs such as stability, bioavailability, and insufficient exposure to the hard-to-reach bacterial drug targets. Although size is a vital colloidal feature of nanoparticles that governs biological interactions, the absence of well-defined size control technology has hampered the investigation of optimal nanoparticle size for targeting bacterial cells. Previously, we identified a lead antichlamydial compound JO146 against the high temperature requirement A (HtrA) protease, a promising antibacterial target involved in protein quality control and virulence. Here, we reveal that JO146 was active against Helicobacter pylori with a minimum bactericidal concentration of 18.8–75.2 µg/mL. Microfluidic technology using a design of experiments approach was utilized to formulate JO146-loaded poly(lactic-co-glycolic) acid nanoparticles and explore the effect of the nanoparticle siz...

Journal of Fungi

Target-based azole resistance in Candida albicans involves overexpression of the ERG11 gene encod... more Target-based azole resistance in Candida albicans involves overexpression of the ERG11 gene encoding lanosterol 14α-demethylase (LDM), and/or the presence of single or multiple mutations in this enzyme. Overexpression of Candida albicans LDM (CaLDM) Y132H I471T by the Darlington strain strongly increased resistance to the short-tailed azoles fluconazole and voriconazole, and weakly increased resistance to the longer-tailed azoles VT-1161, itraconazole and posaconazole. We have used, as surrogates, structurally aligned mutations in recombinant hexahistidine-tagged full-length Saccharomyces cerevisiae LDM6×His (ScLDM6×His) to elucidate how differential susceptibility to azole drugs is conferred by LDM of the C. albicans Darlington strain. The mutations Y140H and I471T were introduced, either alone or in combination, into ScLDM6×His via overexpression of the recombinant enzyme from the PDR5 locus of an azole hypersensitive strain of S. cerevisiae. Phenotypes and high-resolution X-ray c...

High temperature requirement A (HtrA) serine proteases have emerged as a novel class of antibacte... more High temperature requirement A (HtrA) serine proteases have emerged as a novel class of antibacterial target, which are crucial in protein quality control and are involved in the pathogenesis of a wide array of bacterial infections. Previously, we demonstrated that HtrA in Chlamydia is essential for bacterial survival, replication and virulence. Here, we report a new series of proline (P2)-modified inhibitors of Chlamydia trachomatis HtrA (CtHtrA) developed by proline ring expansion and Cγ-substitutions. The structure-based drug optimization process was guided by molecular modelling and in vitro pharmacological evaluation of inhibitory potency, selectivity and cytotoxicity. Compound 25 from the first-generation 4-substituted proline analogues increased antiCtHtrA potency and selectivity over human neutrophil elastase (HNE) by approximately 6- and 12-fold, respectively, relative to the peptidic lead compound 1. Based on this compound, second-generation substituted proline residues co...

Pharmaceuticals

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone dea... more Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in ...

European Journal of Immunology

Mucosal associated invariant T (MAIT) cells are innate like T lymphocytes that are abundant in mu... more Mucosal associated invariant T (MAIT) cells are innate like T lymphocytes that are abundant in mucosal tissues and the liver where they can respond rapidly to a broad range of riboflavin producing bacterial and fungal pathogens. Neutrophils, which are recruited early to sites of infection, play a non redundant role in pathogen clearance and are crucial for controlling infection. The interaction of these two cell types is poorly studied. Here, we investigated both the effect of neutrophils on MAIT cell activation and the effect of activated MAIT cells on neutrophils. We show that neutrophils suppress the activation of MAIT cells by a cell contact and H2O2 dependent mechanism. Moreover, highly activated MAIT cells were able to produce high levels of TNFα that induced neutrophil death. We therefore provide evidence for a negative regulatory feedback mechanism in which neutrophils prevent over-activation of MAIT cells and, in turn, MAIT cells limit neutrophil survival.

Bioorganic & Medicinal Chemistry

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells which can be stim... more Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells which can be stimulated either via their T cell receptor (TCR) or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as Toll-like receptor agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-D-ribitylaminouracil/methylglyoxal (5-A-RU/MG). We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-A-RU/MG-stimulated MAIT cells. Similarly, influenza vir...

Medicinal Research Reviews

European Journal of Medicinal Chemistry

Organic letters, Jan 3, 2017

Three cinnamyl ether spacers (non-methyl, α-methyl, and γ-methyl) for caging of phenols have been... more Three cinnamyl ether spacers (non-methyl, α-methyl, and γ-methyl) for caging of phenols have been synthesized and are physiologically stable. When triggered, the γ-methyl spacer releases phenols (pKa 7.8 and 9.8) with a t1/2 < 30 s and <2 min in aqueous and aqueous-organic solvent, respectively. The α-methyl spacer releases a phenol (pKa 7.8) with a t1/2 = 27 and 54 min. For the γ-methyl spacer, the results suggest the presence of a resonance and inductively stabilized aza-cinnamyl methide.