Anthelmintics for drug repurposing : opportunities and challenges

Drug repositioning is defined as a process to identify a new application for drugs. This approach is critical as it takes advantage of well-known pharmacokinetics, pharmacodynamics, and toxicity profiles of the drugs; thus, the chance of their future failure decreases, and the cost of their development and the required time for their approval are reduced. Anthelmintics, which are antiparasitic drugs, have recently demonstrated promising anticancer effects in vitro and in vivo. This literature review focuses on the potential of anthelmintics for repositioning in the treatment of cancers. It also discusses their pharmacokinetics and pharmacodynamics as antiparasitic drugs, proposed anticancer mechanisms, present development conditions, challenges in cancer therapy, and strategies to overcome these challenges

Camel milk as an alternative treatment regimen for diabetes therapy

Camel milk is a valuable source of nutrition with a wide range of therapeutic effects. Its unique composition helps to regulate the blood glucose level. The current study is aimed to evaluate the antidiabetic and hepatoprotective effects, as well as lipid profile restoration of camel milk in the diabetic mouse model. This innovative study evaluates the therapeutic effects of camel milk in diabetic mice by simultaneous measurement of blood glucose, HbA1c, ALT, AST, TG, cholesterol, and histopathological studies. The results showed that camel milk has significantly reduced blood glucose, HbA1c (p < .001), aspartate transaminase (AST), alanine transaminase (ALT) (p < .01), triglyceride (TG), and cholesterol (p < .01), compared to that in the diabetic control group. Also, the therapeutic effects of camel milk were completely comparable with the antidiabetic drug glibenclamide. The results of this study suggest that camel milk could be used as a proper alternative treatment regimen for diabetes therapy

GLP-1 peptide analogs for targeting pancreatic beta cells

Loss or dysfunction of the pancreatic beta cells or insulin receptors leads to diabetes mellitus (DM). This usually occurs over many years; therefore, the development of methods for the timely detection and clinical intervention are vital to prevent the development of this disease. Glucagon-like peptide-1 receptor (GLP-1R) is the receptor of GLP-1, an incretin hormone that causes insulin secretion in a glucose-dependent manner. GLP-1R is highly expressed on the surface of pancreatic beta cells, providing a potential target for bioimaging. In this review, we provide an overview of various strategies, such as the development of GLP-1R agonists (e.g., exendin-4), and GLP-1 sequence modifications for GLP-1R targeting for the diagnosis and treatment of pancreatic beta cell disorders. We also discuss the challenges of targeting pancreatic beta cells and strategies to address such challenges

Optimized methods for the production and bioconjugation of site-specific, alkyne-modified glucagon-like peptide-1 (GLP-1) analogs to azide-modified delivery platforms using copper-catalyzed alkyne-azide cycloaddition

This study aimed to develop and optimize chemistries to produce alkyne-modified glucagon-like peptide1(7−36)-amide (GLP-1(7−36)-NH2) libraries, which could be rapidly and efficiently conjugated to other components and screened to identify compounds with the best drug delivery properties, as potential treatments for type 2 diabetes or obesity. For this purpose, the Lys26 (K26) side-chain, and the amino (N)- and carboxy (C)-termini of a dipeptidyl peptidase 4 (DPPIV)- resistant GLP-1 sequence (GLP-1(7−36;A8G)-NH2), were modified with an alkyne (4-pentynoic acid or propiolic acid). These analogs were characterized with respect to human GLP-1 receptor (hGLP-1R) agonist activity, effects on cell viability and human serum stability, revealing that these modifications maintained low (N-terminal; EC50 1.5 × 10−9 M) to subnanomolar (C-terminal and K26, ∼4 × 10−10 M) agonist activity toward hGLP-1, had no effect on cell viability, and for the N-terminal and K26 modifications, increased human serum proteolytic stability (t1/2 > 24 h). Copper-catalyzed azide−alkyne cycloaddition (CuAAC) reaction conditions were investigated using the Cterminal modified GLP-1 analog and an azide-modified model lipid peptide, with respect to the effects of altering the azide/alkyne ratio, cosolvents, temperature, reducing agents, Cu(I)-stabilizing ligand, copper source, and the concentrations of reagents/reactants, in order to identify general conditions that provide fast reactions and high yields. A 1:2 azide−alkyne (lipid:GLP-1 peptide) and 4:1 sodium ascorbate/copper sulfate molar ratio in 65% v/v DMSO−water at room temperature, in the absence of Cu(I)-stabilizing ligands (THPTA or L-histidine) and buffers (phosphate, pH 7), provided the best yields. This work reports a library of characterized GLP-1 analogs and chemistries for their attachment to other species, providing useful tools to improve GLP-1 delivery and pharmacology (e.g., through conjugation to other species that lower blood glucose, increase the duration of action, or enable delivery via a nonparenteral route)

Developing GLP-1 conjugated self-assembling nanofibers using copper-catalyzed alkyne-azide cycloaddition and evaluation of their biological activity

Glucagon-like peptide-1 GLP-1 is a gut-derived peptide secreted from pancreatic β-cells that reduces blood glucose levels and body weight; however, native GLP-1 (GLP-1(7−36)-NH2 and GLP1(7−37)) have short in vivo circulation half-lives (∼2 min) due to proteolytic degradation and rapid renal clearance due to its low molecular weight (MW; 3297.7 Da). This study aimed to improve the proteolytic stability and delivery properties of glucagon-like peptide-1 (GLP-1) through modifications that form nanostructures. For this purpose, N- (NtG) and C-terminal (CtG), and Lys26 side chain (K26G) alkyne-modified GLP-1 analogues were conjugated to an azide-modified lipidic peptide (L) to give N-L, C-L, and K-26-L, respectively; or CtG was conjugated with a fibrilizing self-assembling peptide (SAP) (AEAEAKAK)3 to yield C-S, using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). N-L demonstrated the best serum stability (t1/2 > 48 h) compared to K-26-L (44 h), C-L (20 h), C-S (27 h), and the parental GLP-1(7−36;A8G)-NH2 (A8G) (19 h) peptides. Each conjugate demonstrated subnanomolar hGLP-1RA potency, and none demonstrated toxicity toward PC-3 cells at concentrations up to 1 μM. Each analogue was observed by transmission electron microscopy to form fibrils in solution. K-26-L demonstrated among the best human serum stability (t1/2 = 44 h) and similar hGLP-1RA potency (EC50 48 pM) to C-S. In conclusion, this study provided an alternative to lipid modification, i.e., fibrillizing peptides, that could improve pharmacokinetic parameters of GLP-1

Sortase A (SrtA) inhibitors as an alternative treatment for superbug infections

Virulence factor, sortase A (SrtA), has crucial roles in the pathogenesis of Gram-positive superbugs. SrtAis a bacterial cell membrane enzyme that anchors crucial virulence factors to the cell wall surface of Gram-positive bacteria. SrtA is not necessary for bacterial growth and viability and is conveniently accessible in the cell membrane; therefore, it is an ideal target for antivirulence drug development. In this review, we focus on antimicrobial resistance (AMR)-expressing bacteria and SrtA as a potential target for overcoming AMR. The mechanism of action of SrtA and its inhibition by various types of inhibitors, such as synthetic small molecules, peptides, and natural products, are provided. Future SrtA research perspectives for alternative drug development to antibiotics are also proposed

Microfluidic assembly of pomegranate-like hierarchical microspheres for efflux regulation in oral drug delivery

Herein, a multi-functional nano-in-micro hierarchical microsphere system is demonstrated for controlling the intestinal efflux pumps that affect the oral bioavailability of many therapeutic drugs. The hierarchical particles were generated by a co-flow microfluidic device and consisted of porous silica nanoparticles packed in Eudragit® polymeric matrix. Meropenem (MER), a last-resort antibacterial drug, was loaded into porous silica (MCM-48) with a loading capacity of 34.3 wt%. In this unique materials combination, MCM-48 enables ultrahigh loading of a hydrophilic MER, while the Eudragit® polymers not only protect MER from gastric pH but also act as an antagonist for p-glycoprotein protein efflux pumps to reduce the efflux of MER back into the gastrointestinal lumen. We investigated the in-vitro temporal MER release and bidirectional (absorptive and secretory) drug permeation model across the Caco-2 monolayer. The bioavailability of MER was significantly improved by all of the prepared formulations (i.e. increased absorptive transport and reduced secretory transport). The Eudragit® RSPO formulated MER-MCM showed the best performance with an efflux ratio (i.e. secretory transport/absorptive transport) of 0.35, which is 7.4 folds less than pure MER (2.62). Lastly, the prepared formulations were able to retain the antibacterial activity of MER against Staphylococcus aureus and Pseudomonas aeruginosa