Antimicrobial peptide developed with machine learning sequence optimization targets drug resistant Staphylococcus aureus in mice.

As antimicrobial resistance rises, new antibacterial candidates are urgently needed. Using sequence space information from over 14,743 functional antimicrobial peptides (AMPs), we improved the antimicrobial properties of citropin 1.1, an AMP with weak antimethicillin resistant Staphylococcus aureus (MRSA) activity, producing a short and potent antistaphylococcal peptide, CIT-8 (13 residues).

Further Structure-Activity Relationship of G Protein-Gated Inwardly Rectifying Potassium Channels 1/2 Activators: Synthesis and Biological Characterization of In Vitro Tool Compounds.

The work presented herein outlines the ongoing structure-activity relationship studies centered around a potent, efficacious, and selective activators of the G protein-gated inwardly rectifying potassium channels (GIRK)1/2 channel. Optimization studies centered around the pyrazole privileged scaffold, the N-1-position of the pyrazole, and the right-hand ether. The work confirms the necessity of the pyrazole, and a more potent GIRK1/2 activator is identified with ≈12-fold selectivity against GIRK1/4.

Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.

Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure-activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels.

Structure-activity relationship of isoprenoid triazole bisphosphonate-based geranylgeranyl diphosphate synthase inhibitors: Effects on pharmacokinetics, biodistribution, and hepatic transporters.

Geranylgeranyl diphosphate synthase produces the isoprenoid geranylgeranyl diphosphate, which is used in protein geranylgeranylation. Our previous work illustrates that geranylgeranyl diphosphate synthase inhibitors (GGSIs) disrupt Rab-mediated protein trafficking in cells, inducing the unfolded protein response pathway and apoptosis. Structure-function studies of our GGSIs, which are isoprenoid triazole bisphosphonates, have revealed a complex relationship between GGSI structure and enzymatic, cellular, and in vivo activities.

Coenzyme Q deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons.

Coenzyme Q (CoQ) is a critical component of the mitochondrial respiratory chain. CoQ deficiencies cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ involvement in several biological processes.

Development and Validation of an LC-MS/MS Assay for the Quantitation of MO-OH-Nap Tropolone in Mouse Plasma: Application to In Vitro and In Vivo Pharmacokinetic Studies.

A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of MO-OH-Nap tropolone (MO-OH-Nap) in mouse plasma. MO-OH-Nap is an α-substituted tropolone with anti-proliferative properties in various cancer cell lines. Detection and separation of analytes was achieved on an ACE Excel C18 (1.

Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors.

A series of 7-substituted coumarin derivatives have been characterized as pan-aldo-keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7-hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition.

Polymer-Based Drug Delivery Systems for Cancer Therapeutics.

Chemotherapy together with surgery and/or radiotherapy are the most common therapeutic methods for treating cancer. However, the off-target effects of chemotherapy are known to produce side effects and dose-limiting toxicities. Novel delivery platforms based on natural and synthetic polymers with enhanced pharmacokinetic and therapeutic potential for the treatment of cancer have grown tremendously over the past 10 years.

Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma.

Background: Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor prognoses and therapy resistance. However, MYC itself has been one of the most challenging targets for cancer treatment. Here, we identify a novel marinopyrrole natural derivative, MP1, that shows desirable anti-MYC and anti-cancer activities in MB.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates.

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity.

Investigation of the activity of a novel tropolone in osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types.

Chemical remodeling of the mycomembrane with chain-truncated lipids sensitizes mycobacteria to rifampicin.

The outer mycomembrane of and related pathogens is a robust permeability barrier that protects against antibiotic treatment. Here, we demonstrate that synthetic analogues of the mycomembrane biosynthetic precursor trehalose monomycolate bearing truncated lipid chains increase permeability of cells and sensitize them to treatment with the first-line anti-tubercular drug rifampicin. The reported strategy may be useful for enhancing entry of drugs and other molecules to mycobacterial cells, and represents a new way to study mycomembrane structure and function.

Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis.

Background: Posttraumatic stress disorder (PTSD) is a mental health condition triggered by exposure to traumatic events in an individual's life. Patients with PTSD are also at a higher risk for comorbidities. However, it is not well understood how PTSD affects human health and/or promotes the risk for comorbidities.

Simultaneous LC-MS/MS method for the quantitation of Azithromycin, Hydroxychloroquine and its metabolites in SARS-CoV-2(-/ +) populations using dried blood spots.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, efforts were made to test the SARS-CoV-2 antiviral efficacy of repurposed medications that were already approved and available for other indications, including hydroxychloroquine (HCQ) and azithromycin (AZI). To reduce the risk of SARS-CoV-2 exposure for clinical-trial study participants and to conform with lockdowns and social distancing guidelines, biospecimen collection for HCQ and AZI included at-home dried blood spot (DBS) collection rather than standard venipuncture by trained clinicians.

Pharmacokinetics of Moxidectin combined with Albendazole or Albendazole plus Diethylcarbamazine for Bancroftian Filariasis.

Moxidectin (MOX) is a milbemycin endectocide recently approved by the U.S. FDA for the treatment of onchocerciasis in persons at least 12 years of age.

Aldo-Keto Reductase 1C3 Inhibitor Prodrug Improves Pharmacokinetic Profile and Demonstrates In Vivo Efficacy in a Prostate Cancer Xenograft Model.

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in castration-resistant prostate cancer where it acts to drive proliferation and aggressiveness by producing androgens. The reductive action of the enzyme leads to chemoresistance development against various clinical antineoplastics across a range of cancers. Herein, we report the continued optimization of selective AKR1C3 inhibitors and the identification of , a potent AKR1C3 inhibitor (IC = 51 nM) with >1216-fold selectivity for AKR1C3 over closely related isoforms.

A linked physiologically based pharmacokinetic model for hydroxychloroquine and metabolite desethylhydroxychloroquine in SARS-CoV-2(-)/(+) populations.

Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)-approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well-established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states.

LC-MS/MS method for the quantitation of a dual PI3K/BRD4 inhibitor SF2523 in mouse plasma: Application to plasma protein binding and metabolism studies.

A sensitive and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of dual PI3K/BRD4 inhibitor SF2523 in mouse plasma. The analysis was performed on a UPLC system connected to a Shimadzu 8060 mass spectrometer by electrospray ionization in positive multiple reaction monitoring mode. Chromatographic separation was carried out on an ACE Excel C column with a gradient elution containing 0.

A Simultaneous Extraction/Derivatization Strategy for Quantitation of Vitamin D in Dried Blood Spots Using LC-MS/MS: Application to Biomarker Study in Subjects Tested for SARS-CoV-2.

Vitamin D plays a critical role in bone development and maintenance, and in other physiological functions. The quantitation of endogenous levels of individual vitamin D and its metabolites is crucial for assessing several disease state conditions. With cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to the coronavirus disease 2019 (COVID-19) pandemic, there are several studies that have associated lower levels of serum vitamin D with severity of infection in COVID-19 patients.

Biological Evaluation of the Antibacterial Retinoid CD437 in Cutibacterium acnes Infection.

Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and 16 other retinoid analogs as potential anti- compounds and found that CD437 displayed the highest antimicrobial activity with an MIC against (ATCC 6919 and HM-513) of 1 μg/mL. CD437 demonstrated an MBC of 2 μg/mL compared to up to 64 μg/mL for the retinoid adapalene and up to 16 μg/mL for tetracycline, which are commonly used clinically to treat acne.

Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis.

Colorectal cancer (CRC) is a leading cause of the cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling.

Piglet cardiopulmonary bypass induces intestinal dysbiosis and barrier dysfunction associated with systemic inflammation.

The intestinal microbiome is essential to human health and homeostasis, and is implicated in the pathophysiology of disease, including congenital heart disease and cardiac surgery. Improving the microbiome and reducing inflammatory metabolites may reduce systemic inflammation following cardiac surgery with cardiopulmonary bypass (CPB) to expedite recovery post-operatively. Limited research exists in this area and identifying animal models that can replicate changes in the human intestinal microbiome after CPB is necessary.