Nunzia Cristiano, PhD’s Post

Scientists use lipid nanoparticles to get proteins and nucleic acids into cells, and emerging therapeutics and vaccines use them too. You add them to cells, and a little while later a gene gets knocked down or the cells are making spike protein. But -- how much of your protein actually got into the cells in the first place? Turns out, this is a very hard measurement to make... Kritzer Lab graduate student Jing Wang (assisted by former Kritzer Lab MS student Shiying (Maple) Zhang and nanoparticle experts Yamin Li and Qiaobing Xu) used a new assay, the Chloroalkane Penetration Assay, to make this measurement and compare it to more common measures of cell uptake and bioactivity. She even used CAPA as a screen to find lipidoids with improved delivery! Read about it now in Biochemistry, part of a special issue on drug delivery!!! https://lnkd.in/dv4z7nt3

Lipidomics harmonization --- In 2017, as the field of lipidomics advanced, a pivotal moment unfolded in the community—a thorough self-evaluation. The focus was a comprehensive interlaboratory comparison using Standard Reference Material (SRM) 1950 – Metabolites in Frozen Human Plasma, a commercially available reference material. An impressive 31 diverse laboratories, including Lipotype's lab, engaged, each employing a distinct lipidomics workflow. Across the board, a total of 1,527 lipids were meticulously measured. The study sought consensus location estimates and uncertainties for 339 of these lipids, measured by five or more participating laboratories. These lipids in SRM 1950 have since become historical benchmarks, offering guidance for quality control and method validation within the community. Read the publication here: https://lnkd.in/ehWWJfjJ #research #lipid #lipidomics #LipidMetabolism #lipotype #lipidome #NISTstudy #PlasmaLipidome

Many emerging disease and cancer therapies are based on “small molecules,” compounds that, when given as drugs, induce certain therapeutic effects by binding to their targets. But knowing which small molecule will bind where is a difficult question — one not infrequently answered by sheer chance. In a research partnership with University of Pennsylvania Perelman School of Medicine's Luca Busino, Ph.D., Wistar’s Salvino lab — led by Dr. Joseph Salvino — has co-developed a new approach for systematically identifying which small molecules bind to which drug targets. Their new methodology, called TAP-DAP (Tandem-Affinity Purification for identification of Drug-Binding Proteins), not only allows researchers to systematically identify drug–protein interactions — it also indexes “off-target” interactions. By indicating where a small molecule could bind in addition to its intended target, TAP-DAP can help researchers anticipate whether a drug candidate might have either unintended toxicity or a therapeutic synergy. Read the full paper from ACS Chemical Biology here: https://bit.ly/497n9YA #drugdiscovery #research #smallmolecule #pharmacology

IMiD small molecule library ChemDiv’s collection of imide-like compounds for the discovery of PROTAC and molecular glue molecules contains 2,000 entries. Imide-like compounds provide the scientific background for discovering and developing PROTACs and molecular glue drug compounds, two innovative strategies in targeted protein degradation. These compounds act as crucial connectors or "glues" that facilitate the interaction between target proteins and the cellular degradation machinery via engagement with E3 ligase. https://lnkd.in/eTEBxRrY #IMiD

Our paper on metabolite identification and characterization of #Ostarine, a selective androgen receptor modulator commonly used as doping agent, is available at; https://lnkd.in/d-Kdj4vm, part of the special issue on Molecular Markers in Forensic Science as Elements of Evidence. Kintz and Gheddar early demonstrated a case of cross-contamination where the athletes involved were suspended, highlighting perhaps why "contextual interpretation" may be important in certain cases, although, that could be a slippery slope if examiner bias starts to creep in. Find Kintz & Gheddar, 2024 here: https://lnkd.in/dGAD8PjP #ToxWatch #CleanSports #Forensics

In this 2022 paper "In silico identification of a β2-adrenoceptor allosteric site that selectively augments canonical β2AR-Gs signaling and function", SILCS was used to identify a novel allosteric site on the β2-adrenoceptor. This allows for selective enhancement of β2AR-Gs signaling, offering potential for targeted therapeutic interventions with fewer side effects. This study shows the applicability of SILCS to membrane proteins, as protein flexibility is taken into account during the simulations." #compchem #SILCS #membraneproteins

#ICYMI: Sapient has expanded our metabolite identification capabilities to further enhance & accelerate small molecule #biomarkerdiscovery. Read the full #pressrelease to learn how our comprehensive Metabolite Standards Library, comprised of >10,000 chemical reference standards and enabling Tier 1 identifications for more than 1,000 metabolites and lipids routinely measured in human plasma, brings critical scientific value to discovery #metabolomics and #lipidomics screenings in two key ways: 1) Providing the highest possible confidence to #biomarker identification using multi-parameter data 2) Enabling putative structural insights for hundreds to thousands of additional unknown #metabolites and #lipids, enabling advancement of novel discoveries Read more: https://lnkd.in/gNZZScf3

Many emerging disease and cancer therapies are based on “small molecules,” compounds that, when given as drugs, induce certain therapeutic effects by binding to their targets. But knowing which small molecule will bind where is a difficult question — one not infrequently answered by sheer chance. In a research partnership with University of Pennsylvania Perelman School of Medicine's Luca Busino, Ph.D., Wistar’s Salvino lab — led by Dr. Joseph Salvino — has co-developed a new approach for systematically identifying which small molecules bind to which drug targets. Their new methodology, called TAP-DAP (Tandem-Affinity Purification for identification of Drug-Binding Proteins), not only allows researchers to systematically identify drug–protein interactions — it also indexes “off-target” interactions. By indicating where a small molecule could bind in addition to its intended target, TAP-DAP can help researchers anticipate whether a drug candidate might have either unintended toxicity or a therapeutic synergy. Read the full paper from ACS Chemical Biology here: https://bit.ly/497n9YA #drugdiscovery #research #smallmolecule #pharmacology

Working in the #drugdiscovery industry means that we don’t always get to talk about all the work we do or touch. A couple of months ago, a team from AbbVie published their work titled “Targeting the Tyrosine Kinase 2 (TYK2) Pseudokinase Domain: Discovery of the Selective TYK2 Inhibitor ABBV-712” in #JournalOfMedicinalChemistry: https://lnkd.in/eyVeVURX In this paper, they rationally designed #TYK2inhibitors. Along the way, they encountered multiple #DrugDrugInteraction challenges of specific #CytochromesP450 which led them to change their #drugdesign approach. They used our site of metabolism prediction tool, #IMPACTS to locate their compounds' initial oxidation site and to optimize their compounds by reducing their affinity for #CYP3A4, which they achieved. Explore how IMPACTS and our suite of software tools can significantly enhance your ability to tackle #drugdiscovery challenges: https://lnkd.in/gC-qgHyk. You can delve into some of our research using IMPACTS in these papers: https://lnkd.in/eWqRaSAa and https://lnkd.in/eR7RP8rA.

Recently, I read two papers on lymphatic filariasis (LF) discussing Cofactor-independent phosphoglycerate mutase (iPGM) as a potential drug target for LF, published in Oxford Academy-2024 (PMID:37481257) and Bentham Publications-2023 (PMID:31244425). I'm glad to have discovered this back in 2015. Here are some insights from my original article if you're interested: https://lnkd.in/eTdnyXs3. We delved into the structural stability of Wb-iPGM through molecular dynamics simulations, shedding light on its interaction with cofactors 3-phosphoglycerate (3PGA) and Mn2+ ions. Notably, we unveiled domain motions and the catalytic significance of Mn2+ ions, offering insights crucial for drug development. #LymphaticFilariasis #DrugDiscovery #ResearchInsights #Structuralbiology #simulations #bioinformatics #computationalbiology