Novel Autotaxin Inhibitor ATX-1d Significantly Enhances Potency of Paclitaxel-An In Silico and In Vitro Study.

The development of drug resistance in cancer cells poses a significant challenge for treatment, with nearly 90% of cancer-related deaths attributed to it. Over 50% of ovarian cancer patients and 30-40% of breast cancer patients exhibit resistance to therapies such as Taxol. Previous literature has shown that cytotoxic cancer therapies and ionizing radiation damage tumors, prompting cancer cells to exploit the autotaxin (ATX)-lysophosphatidic acid (LPA)-lysophosphatidic acid receptor (LPAR) signaling axis to enhance survival pathways, thus reducing treatment efficacy.

Synthesis and Characterization of Derivatives of the Antifungal Peptoid RMG8-8.

Cryptococcal meningitis, caused by the fungal pathogen , is a devastating disease with a mortality rate of over 80%. Due to the increasing prevalence of resistance to antifungals and the high mammalian toxicity of current treatments, the development of new antifungal therapies is vital. In an effort to improve the biological properties of a previously discovered antifungal peptoid, termed RMG8-8, an iterative structure-activity relationship study was conducted.

Development of an Anti-Biofilm Screening Technique Leads to the Discovery of a Peptoid with Efficacy against .

Bacteria and fungi can secrete and reside within a complex polysaccharide matrix, forming a biofilm that protects these pathogens from the immune response and conventional antibiotics. Because many microbial pathogens grow within biofilms in clinical settings, there is a need for antimicrobial agents effective against biofilm-protected infections. We report the adaptation of a phenotypic high-throughput assay for discovering antimicrobial peptoids toward the screening of combinatorial libraries against established biofilms.

Discovery and Characterization of a Rapidly Fungicidal and Minimally Toxic Peptoid against .

A limited number of antifungals are available to treat infections caused by fungal pathogens such as and . Current clinical antifungals are generally toxic, and increasing resistance to these therapies is being observed, necessitating new, effective, and safe antifungals. Peptoids, or N-substituted glycines, have shown promise as antimicrobial agents against bacteria, fungi, and parasites.

Recent advances in the development of anti-infective peptoids.

In the search for new sources of antimicrobials many researchers have investigated antimicrobial peptides (AMPs) as templates for the design of innovative therapeutics. However, efforts to develop AMPs in this area has been severely hampered by their inherent susceptibility to enzymatic degradation. Given this only a handful of AMPs are currently in clinical trials.

Evaluation of peptoid mimics of short, lipophilic peptide antimicrobials.

Introduction: Antimicrobial peptides are proving to be promising lead compounds for therapeutics. The major disadvantage of antimicrobial peptides is their proteolytic instability in the body, with half-lives averaging less than an hour. Peptoids, or N-substituted glycines, have emerged as a promising field of peptidomimetics by retaining the beneficial properties of antimicrobial peptides while improving their stability.

Toward a clinical antifungal peptoid: Investigations into the therapeutic potential of AEC5.

Cryptococcus neoformans is a fungal pathogen that causes cryptococcal meningitis in immunocompromised individuals. Existing antifungal treatment plans have high mammalian toxicity and increasing drug resistance, demonstrating the dire need for new, nontoxic therapeutics. Antimicrobial peptoids are one alternative to combat this issue.

Improved potency and reduced toxicity of the antifungal peptoid AEC5 through submonomer modification.

As proteolytically stable peptidomimetics, peptoids could serve as antifungal agents to supplement a therapeutic field wrought with toxicity issues. We report the improvement of an antifungal peptoid, AEC5, through an iterative structure-activity relationship study. A sarcosine scan was used to first identify the most pharmacophorically important peptoid building blocks of AEC5, followed by sequential optimization of each building block.

Response to comment on "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis".

The citrullinome cargo in neutrophil extracellular traps varies according to disease condition and stimulation conditions.

Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated proteins. Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblasts (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS, and whether these interactions generate pathogenic anti-citrulline adaptive immune responses.

Evaluating the Effect of Peptoid Lipophilicity on Antimicrobial Potency, Cytotoxicity, and Combinatorial Library Design.

Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the peptoid library agar diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity.

Discovery and Characterization of a Peptoid with Antifungal Activity against .

Studies show there is an increasing rate of fungal infections, especially in immunocompromised patients and treatments for fungal genera, such as , , and , carry significant cytotoxicity with an increasing prevalence of antifungal resistance. We have previously reported a high-throughput assay for identifying peptoids with antimicrobial properties from combinatorial libraries. Here we report the application of this assay in identifying a peptoid with antifungal properties against .

Peptoid Library Agar Diffusion (PLAD) Assay for the High-Throughput Identification of Antimicrobial Peptoids.

Rapid emergence of antimicrobial resistant organisms necessitates equally rapid methods for the development of new antimicrobial compounds. Of recent interest have been mimics of antimicrobial peptides known as antimicrobial peptoids, which exhibit similar potency to the former but with improved proteolytic stability. Presented herein is a high-throughput method to screen libraries of antimicrobial peptoids immobilized on beads embedded into solid media.

Chemical Proteomic Platform To Identify Citrullinated Proteins.

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and are routinely used for disease diagnosis. Protein citrullination is also increased in cancer and other autoimmune disorders, suggesting that citrullinated proteins may serve as biomarkers for diseases beyond RA. To identify these citrullinated proteins, we developed biotin-conjugated phenylglyoxal (biotin-PG).

Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.

PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.

A FluoPol-ABPP PAD2 high-throughput screen identifies the first calcium site inhibitor targeting the PADs.

The protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of peptidyl-arginine to form peptidyl-citrulline in a process termed deimination or citrullination. PADs likely play a role in the progression of a range of disease states because dysregulated PAD activity is observed in a host of inflammatory diseases and cancer. For example, recent studies have shown that PAD2 activates ERα target gene expression in breast cancer cells by citrullinating histone H3 at ER target promoters.

D-amino acid based protein arginine deiminase inhibitors: Synthesis, pharmacokinetics, and in cellulo efficacy.

The protein arginine deiminases (PADs) are known to play a crucial role in the onset and progression of multiple inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and cancer. However, it is not known how each of the five PAD isozymes contributes to disease pathogenesis. As such, potent, selective, and bioavailable PAD inhibitors will be useful chemical probes to elucidate the specific roles of each isozyme.

The protein arginine deiminases: Structure, function, inhibition, and disease.

The post-translational modification of histones has significant effects on overall chromatin function. One such modification is citrullination, which is catalyzed by the protein arginine deiminases (PADs), a unique family of enzymes that catalyzes the hydrolysis of peptidyl-arginine to form peptidyl-citrulline on histones, fibrinogen, and other biologically relevant proteins. Overexpression and/or increased PAD activity is observed in several diseases, including rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease, and cancer.

Seeing citrulline: development of a phenylglyoxal-based probe to visualize protein citrullination.

Protein arginine deiminases (PADs) catalyze the hydrolysis of peptidyl arginine to form peptidyl citrulline. Abnormally high PAD activity is observed in a host of human diseases, but the exact role of protein citrullination in these diseases and the identities of specific citrullinated disease biomarkers remain unknown, largely because of the lack of readily available chemical probes to detect protein citrullination. For this reason, we developed a citrulline-specific chemical probe, rhodamine-phenylglyoxal (Rh-PG), which we show can be used to investigate protein citrullination.

Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation.

Cofactors for estrogen receptor α (ERα) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found that stimulation of ERα-positive cells with 17β-estradiol (E2) promotes global citrullination of histone H3 arginine 26 (H3R26) on chromatin. Additionally, we found that the H3 citrulline 26 (H3Cit26) modification colocalizes with ERα at decondensed chromatin loci surrounding the estrogen-response elements of target promoters.

Synthetic lectin arrays for the detection and discrimination of cancer associated glycans and cell lines.

Aberrant glycosylation is a hallmark of various disease states, including cancer, and effective detection and discrimination between healthy and diseased cells is an important challenge for the diagnosis and treatment of many diseases. Here, we describe the use of boronic acid functionalized synthetic lectins (SLs) in an array format for the differentiation of structurally similar cancer associated glycans and cancer cell lines; discrimination is based on subtle variations in glycosylation patterns. We further demonstrate the utility of our SLs in recognizing glycoproteins with up to 50-fold selectivity, even in 95% human serum.

Boronic acid functionalized peptidyl synthetic lectins: combinatorial library design, peptide sequencing, and selective glycoprotein recognition.

Aberrant glycosylation of cell membrane and secreted glycoproteins is a hallmark of various disease states, including cancer. The natural lectins currently used in the recognition of these glycoproteins are costly, difficult to produce, and unstable toward rigorous use. Herein we describe the design and synthesis of several boronic acid functionalized peptide-based synthetic lectin (SL) libraries, as well as the optimized methodology for obtaining peptide sequences of these SLs.

A combinatorial approach to characterize the substrate specificity of protein arginine methyltransferase 1.

The dysregulation of protein arginine methyltransferases (PRMTs) is implicated in a wide variety of disease states. Here we report the design, synthesis, and screening of a combinatorial peptide library used to characterize the substrate specificity of PRMT1. The information gained from this approach was used to develop a PRMT1 inhibitor with enhanced selectivity.