CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.

Visceral leishmaniasis is a life-threatening parasitic disease, but current antileishmanial drugs have severe drawbacks. Antifungal azoles inhibit the activity of cytochrome P450 (CYP) 51 enzymes which are responsible for removing the C14α-methyl group of lanosterol, a key step in ergosterol biosynthesis in Leishmania. However, they exhibit varying degrees of antileishmanial activities in culture, suggesting the existence of unrecognized molecular targets.

CYP5122A1 encodes an essential sterol C4-methyl oxidase in and determines the antileishmanial activity of antifungal azoles.

Visceral leishmaniasis, caused by , is a life-threatening parasitic disease, but current antileishmanial drugs are limited and have severe drawbacks. There have been efforts to repurpose antifungal azole drugs for the treatment of infection. Antifungal azoles are known to potently inhibit the activity of cytochrome P450 (CYP) 51 enzymes which are responsible for removing the C14α-methyl group of lanosterol, a key step in ergosterol biosynthesis in .

Sterol profiling of Leishmania parasites using a new HPLC-tandem mass spectrometry-based method and antifungal azoles as chemical probes reveals a key intermediate sterol that supports a branched ergosterol biosynthetic pathway.

Human leishmaniasis is an infectious disease caused by Leishmania protozoan parasites. Current chemotherapeutic options against the deadly disease have significant limitations. The ergosterol biosynthetic pathway has been identified as a drug target in Leishmania.

Structure-activity studies of PTPRD phosphatase inhibitors identify a 7-cyclopentymethoxy illudalic acid analog candidate for development.

Interest in development of potent, selective inhibitors of the phosphatase from the receptor type protein tyrosine phosphatase PTPRD as antiaddiction agents is supported by human genetics, mouse models and studies of our lead compound PTPRD phosphatase inhibitor, 7-butoxy illudalic acid analog 1 (7-BIA). We now report structure-activity relationships for almost 70 7-BIA-related compounds and results that nominate a 7- cyclopentyl methoxy analog as a candidate for further development. While efforts to design 7-BIA analogs with substitutions for other parts failed to yield potent inhibitors of PTPRD's phosphatase, ten 7-position substituted analogs displayed greater potency at PTPRD than 7-BIA.

Fungally Derived Isoquinoline Demonstrates Inducer-Specific Tau Aggregation Inhibition.

The microtubule-associated protein tau promotes the stabilization of the axonal cytoskeleton in neurons. In several neurodegenerative diseases, such as Alzheimer's disease, tau has been found to dissociate from microtubules, leading to the formation of pathological aggregates that display an amyloid fibril-like structure. Recent structural studies have shown that the tau filaments isolated from different neurodegenerative disorders have structurally distinct fibril cores that are specific to the disease.

Visible photorelease of liquid biopsy markers following microfluidic affinity-enrichment.

We detail a heterobifunctional, 7-aminocoumarin photocleavable (PC) linker with unique properties to covalently attach Abs to surfaces and subsequently release them with visible light (400-450 nm). The PC linker allowed rapid (2 min) and efficient (>90%) release of CTCs and EVs without damaging their molecular cargo.

Synthetic Rhamnose Glycopolymer Cell-Surface Receptor for Endogenous Antibody Recruitment.

Synthetic materials capable of engineering the immune system are of great relevance in the fight against cancer to replace or complement the current monoclonal antibody and cell therapy-based immunotherapeutics. Here, we report on antibody recruiting glycopolymers (ARGPs). ARGPs consist of polymeric copies of a rhamnose motif, which can bind endogenous antirhamnose antibodies present in human serum.

Antibody-Drug Conjugate that Exhibits Synergistic Cytotoxicity with an Endosome-Disruptive Peptide.

Antibody-drug conjugates are an important class of cancer therapeutics. These agents generally bind a specific cell surface receptor, undergo receptor-mediated endocytosis, and enter the endosomal-lysosomal system, where the environment in these organelles facilitates the release of a membrane-permeable cytotoxin. By using a membrane-impermeable cytotoxin, we describe here a method that allows the cytotoxicity of an antibody conjugate to be triggered by co-administration with an endosome-disruptive peptide that exhibits low toxicity.

Discovery of Small-Molecule Inhibitors Targeting the E3 Ubiquitin Ligase Activity of the Herpes Simplex Virus 1 ICP0 Protein Using an High-Throughput Screening Assay.

Herpes simplex virus 1 (HSV-1) has infected more than 80% of the population. Reactivation of the virus causes diseases ranging in severity from benign cold sores to fatal encephalitis. Current treatments involve viral DNA replication inhibitors, but the emergence of drug-resistant mutants is observed frequently, highlighting the need for novel antiviral therapies.

High-Throughput Screening for Bacterial Glycosyltransferase Inhibitors.

The enteropathogenic and enterohemorrhagic NleB proteins as well as the SseK proteins are type III secretion system effectors that function as glycosyltransferase enzymes to post-translationally modify host substrates on arginine residues. This modification is unusual because it occurs on the guanidinium groups of arginines, which are poor nucleophiles, and is distinct from the activity of the mammalian -linked -acetylglucosaminyltransferase. We conducted high-throughput screening assays to identify small molecules that inhibit NleB/SseK activity.

Fluorescent mimics of cholesterol that rapidly bind surfaces of living mammalian cells.

Mammalian cells acquire cholesterol, a critical membrane constituent, through multiple mechanisms. We synthesized mimics of cholesterol, fluorescent N-alkyl-3β-cholesterylamine-glutamic acids, that are rapidly incorporated into cellular plasma membranes compared with analogous cholesteryl amides, ethers, esters, carbamates, and a sitosterol analogue. This process was inhibited by ezetimibe, indicating a receptor-mediated uptake pathway.

Gas-phase fragmentation of deprotonated p-hydroxyphenacyl derivatives.

Electrospray ionization of methanolic solutions of p-hydroxyphenacyl derivatives HO-C(6)H(4)-C(O)-CH(2)-X (X = leaving group) provides abundant signals for the deprotonated species which are assigned to the corresponding phenolate anions (-)O-C(6)H(4)-C(O)-CH(2)-X. Upon collisional activation in the gas phase, these anions inter alia undergo loss of a neutral "C(8)H(6)O(2)" species concomitant with formation of the corresponding anions X(-). The energies required for the loss of the neutral roughly correlate with the gas phase acidities of the conjugate acids (HX).

-Hydroxyphenacyl photoremovable protecting groups - Robust photochemistry despite substituent diversity.

A broadly based investigation of the effects of a diverse array of substituents on the photochemical rearrangement of hydroxyphenacyl esters has demonstrated that common substituents such as F, MeO, CN, COR, CONH, and CH have little effect on the rate and quantum efficiencies for the photo-Favorskii rearrangement and the release of the acid leaving group or on the lifetimes of the reactive triplet state. A decrease in the quantum yields across all substituents was observed for the release and rearrangement when the photolyses were carried out in buffered aqueous media at pHs that exceeded the ground-state p of the chromophore where the conjugate base is the predominant form. Otherwise, substituents have only a very modest effect on the photoreaction of these robust chromophores.