Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells

Vaccination has drastically decreased mortality due to coronavirus disease 19 (covid19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies, such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, hydroxypropyl-β-cyclodextrin (HPβCD) was tested in a HEK293T-ACE2hi cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. Exposure of HEK293T-ACEhi cells to concentrations of HPβCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACEhi cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPβCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. These data indicate that HPβCD is a candidate for use as a SARS-CoV-2 prophylactic agent.

Silvia AlboniValentina SeccoBianca PapottiAntonietta VilellaMaria Pia AdorniFrancesca ZimettiLaurent Schaeffertascedda fabioMichele ZoliPascal LeblancErica Villa

See the full article here: Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACEhi Cells

Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery

Today’s cyclodextrin:
Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery
Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumor retention. Here Seoul National University and Chungnam National University report on the design of renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. The optimized cyclodextrin shows a high tumor accumulation and is used for the delivery of doxorubicin and ulixertinib. Higher tumor accumulation and tumor penetration facilitate tumor elimination. The improved antitumor efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.

See the full article here: Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery

Effect of Cosolutes on the Aggregation of a Tau Fragment: A Combined Experimental and Simulation Approach

Having an interest in the applications of novel carbohydrates in neurodegenerative diseases, we applaud this paper on the aggregation of Tau fragments in the presence of different cosolutes, including urea, TMAO, sucrose, and 2-hydroxypropyl-β-cyclodextrin (2-HPβCD).
The intrinsically disordered protein Tau represents the main component of neurofibrillary tangles that are a hallmark of Alzheimer’s disease and is considered to be important for the formation of the β-structure core of the fibrils. 
The remarkable ability of HPβCD to inhibit aggregation represents an extremely promising result for future applications, especially considering the widespread use of this molecule as a drug carrier to the brain and as a solubilizer/excipient in pharmaceutical formulations.
Andrea ArsiccioXikun LiuPritam GangulySteve BurattoMichael Bowers, and Joan-Emma Shea

See the full article here: Effect of Cosolutes on the Aggregation of a Tau Fragment: A Combined Experimental and Simulation Approach

InnoGly COST Action Closing meeting

Tamas Sohajda represented us at the closing meeting of InnoGly a European COST Action aimed at facilitating networking and innovation of glycans in the field of cancer research, autophagy, immunity, and glycosaminoglycans. This was a fantastic experience and the start of several useful collaborations for the future.

U.S. Food and Drug Administration approved Arexvy, the first respiratory syncytial virus (RSV) vaccine

FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine
Today, the U.S. FDA approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States. Arexvy is approved for the prevention of lower respiratory tract disease caused by RSV in individuals 60 years of age and older. RSV is a highly contagious virus that causes infections of the lungs and breathing passages in individuals of all age groups. RSV circulation is seasonal, typically starting during the fall and peaking in the winter. In older adults, RSV is a common cause of lower respiratory tract disease, which affects the lungs and can cause life-threatening pneumonia and bronchiolitis (swelling of the small airway passages in the lungs). According to the U.S. Centers for Disease Control and Prevention, each year in the U.S., RSV leads to approximately 60,000-120,000 hospitalizations and 6,000-10,000 deaths among adults 65 years of age and older. 
GSK’s RSVPreF3 (Arexvy), is a recombinant product that contains a glycoprotein antigen based on the RSV A subgroup and is given with a proprietary adjuvant—the same one in GSK‘s Shingrix shingles (herpes zoster) vaccine—designed to boost the immune response.

See the FDA annucement here

Lilly drug slows Alzheimer’s by 35%, bolstering treatment approach

Lilly’s Alzheimer’s drug donanemab slows cognitive decline by 35% in PhIII
An experimental Alzheimer’s drug developed by Eli Lilly and Company slowed cognitive decline by 35% in a late-stage trial, providing what experts say is the strongest evidence yet that removing sticky amyloid plaques from the brain benefits patients with the fatal disease.
Lilly’s drug, donanemab, met all goals of the trial: It slowed the progression of Alzheimer’s by 35% compared to a placebo in 1,182 people with an early-stage disease whose brains had deposits of two key Alzheimer’s proteins, beta-amyloid as well as intermediate levels of tau, a protein linked with disease progression and brain cell death.

See the article on reuters.com: Lilly drug slows Alzheimer’s by 35%, bolstering treatment approach

Chemical Analysis and Molecular Modelling of Cyclodextrin-Formulated Propofol and Its Sodium Salt to Improve Drug Solubility, Stability and Pharmacokinetics (Cytogenotoxicity)

today’s cyclodextrin:
Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using hydroxypropyl-β-cyclodextrin (HPβCD). The formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.

Benedikt WilhelmsProf. Dr. Jens BroscheitSergey Shityakov

See the full article here: Chemical Analysis and Molecular Modelling of Cyclodextrin-Formulated Propofol and Its Sodium Salt to Improve Drug Solubility, Stability and Pharmacokinetics (Cytogenotoxicity)

Use of cyclodextrins in diseases and disorders involving phospholipid dysregulation

A very recent patent application from ASDERA on using hyproxypropyl-alfa-cyclodextrin formulated with a medium chain fatty acid (ideally a cproic acid derivative) for the ORAL delivery is the CD. Similarly to our interests, the CD itself is proposed to be the therapeutic agent and the oral delivery would open a new solution to treat cancer or a neurodegenerative, cardiovascular, metabolic, inflammatory, autoimmune, age-related, or viral disease or disorder in a subject which is currently only possible via parenteral administration. Keep an eye on Knut M. Wittkowski as his research is highly important. Overcoming the current issues with CD dosing is an unsolved problem in this research area.

See the full patent here: Use of cyclodextrins in diseases and disorders involving phospholipid dysregulation

Fragmentation of DMPC Membranes by a Wedge-Shaped Amphiphilic Cyclodextrin into Bicellar-like Aggregates

Here is another fascinating application of amphiphilic cyclodextrin presented by Université Paris-Saclay and Université de Picardie Jules Verne (Amiens).
Small bilayer lipid aggregates such as bicelles provide useful membrane mimetics for structural studies of biological membranes. Wedge-shaped amphiphilic derivative of trimethyl β-cyclodextrin anchored in bilayers through a lauryl acyl chain (TrimβMLC) is able to induce fragmentation of the multilamellar membranes. DMPC membranes are progressively disrupted by TrimβMLC into small and large micellar aggregates. No membrane orientation and fragmentation were detected with unsaturated POPC membranes, which are able to accommodate the insertion of TrimβMLC without important perturbation.
Michel RouxFrançois-Xavier LegrandVéronique Bonnet et al

See the article here: Fragmentation of DMPC Membranes by a Wedge-Shaped Amphiphilic Cyclodextrin into Bicellar-like Aggregates