Structure of a Cyclic Peptide as an Inhibitor of Transcription: NMR and Molecular Dynamics Simulations.

Background And Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the nanomolar range, which can halt the MTB transcription initiation complex, similar to RIF. Therefore, determining the solution conformation of this peptide is useful in improving the peptide's binding affinity to the RNAP.

Delivery of Neuroregenerative Proteins to the Brain for Treatments of Neurodegenerative Brain Diseases.

Neurodegenerative brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and Parkinson's disease (PD) are difficult to treat. Unfortunately, many therapeutic agents for neurodegenerative disease only halt the progression of these diseases and do not reverse neuronal damage. There is a demand for finding solutions to reverse neuronal damage in the central nervous system (CNS) of patients with neurodegenerative brain diseases.

Mechanism of the blood-brain barrier modulation by cadherin peptides.

Aim: This study was aimed at finding the binding site on the human E-cadherin for Ala-Asp-Thr Cyclic 5 (ADTC5), ADTC7, and ADTC9 peptides as blood-brain barrier modulator (BBBM) for determining their mechanism of action in modulating the blood-brain barrier (BBB).

Methods: ADTC7 and ADTC9 were derivatives of ADTC5 where the Val6 residue in ADTC5 was replaced by Glu6 and Tyr6 residues, respectively. The binding properties of ADTC5, ADTC7, and ADTC9 to the extracellular-1 (EC1) domain of E-cadherin were evaluated using chemical shift perturbation (CSP) method in the two dimensional (2D) H-N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy.

Exploring How Antibody Format Drives Clearance from the Brain.

Monoclonal antibodies (mAbs) have high binding specificity and affinity, making them attractive for treating brain diseases. However, their effectiveness is limited by poor blood-brain barrier (BBB) penetration and rapid central nervous system (CNS) clearance. Our group identified blood-brain barrier modulator (BBBM) peptides that improved mAb penetration across the BBB into the brain.

Correction: Synthesis and anticancer evaluation of [d-Ala]-nocardiotide A.

[This corrects the article DOI: 10.1039/D4RA00025K.].

Selective Uptake of Macromolecules to the Brain in Microfluidics and Animal Models Using the HAVN1 Peptide as a Blood-Brain Barrier Modulator.

Monoclonal antibodies (mAbs) possess favorable pharmacokinetic properties, high binding specificity and affinity, and minimal off-target effects, making them promising therapeutic agents for central nervous system (CNS) disorders. However, their development as effective therapeutic and diagnostic agents for brain disorders is hindered by their limited ability to efficiently penetrate the blood-brain barrier (BBB). Therefore, it is crucial to develop efficient delivery methods that enhance the penetration of antibodies into the brain.

Synthesis and anticancer evaluation of [d-Ala]-nocardiotide A.

Cancer is currently one of the biggest causes of death in the world. Like some microorganisms, cancer cells also develop resistance to various chemotherapy drugs and are termed multidrug resistant (MDR). In this regard, there is a need to develop new alternative anticancer agents.

Evaluation of LFA-1 Peptide-Methotrexate Conjugates in Modulating Endothelial Cell Inflammation and Cytokine Regulation.

Interactions between vascular endothelial cells and inflammatory leukocytes are intermediated via cell adhesion molecules and they become one of the key events for vascular cell injury and development of atherosclerosis. This study evaluated the effects of MTX-peptide conjugates as anti-inflammatory agents on human coronary artery endothelial cells (HCAEC) and Molt-3 T cells. Cyclic peptides, cLABL and cLBEL, were derived from the α- and β-subunits of leukocyte function-associated antigen-1 (LFA-1), respectively.

Immune Modulation by Antigenic Peptides and Antigenic Peptide Conjugates for Treatment of Multiple Sclerosis.

The immune system defends our body by fighting infection from pathogens utilizing both the innate and adaptive immune responses. The innate immune response is generated rapidly as the first line of defense. It is followed by the adaptive immune response that selectively targets infected cells.

Transcription Machinery: A Review on the Mycobacterial RNA Polymerase and Drug Discovery Efforts.

(MTB) is the main source of tuberculosis (TB), one of the oldest known diseases in the human population. Despite the drug discovery efforts of past decades, TB is still one of the leading causes of mortality and claimed more than 1.5 million lives worldwide in 2020.

Spermidine/Spermine N1-Acetyltransferase 1 ()-A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA.

Spermidine/spermine N1-acetyltransferase 1 () responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-si) to selectively knockdown (KD) enzyme in a human glioblastoma cell line.

Structural Design and Synthesis of Novel Cyclic Peptide Inhibitors Targeting Transcription.

Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Although several established antitubercular drugs have been found, various factors obstruct efforts to combat this disease due to the existence of drug-resistance (DR) TB strains, the need for lengthy treatment, and the occurrence of side effects from drug-drug interactions. Rifampicin (RIF) is the first line of antitubercular drugs and targets RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB).

Enhancing Intestinal Absorption of a Model Macromolecule via the Paracellular Pathway using E-Cadherin Peptides.

Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro, were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C).

Doxorubicin-loaded iron oxide nanoparticles for glioblastoma therapy: a combinational approach for enhanced delivery of nanoparticles.

Although doxorubicin (DOX) is an effective anti-cancer drug with cytotoxicity in a variety of different tumors, its effectiveness in treating glioblastoma multiforme (GBM) is constrained by insufficient penetration across the blood-brain barrier (BBB). In this study, biocompatible magnetic iron oxide nanoparticles (IONPs) stabilized with trimethoxysilylpropyl-ethylenediamine triacetic acid (EDT) were developed as a carrier of DOX for GBM chemotherapy. The DOX-loaded EDT-IONPs (DOX-EDT-IONPs) released DOX within 4 days with the capability of an accelerated release in acidic microenvironments.

Non-invasive Brain Delivery and Efficacy of BDNF in APP/PS1 Transgenic Mice as a Model of Alzheimer's Disease.

Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been demonstrated for their potential as a neuroregenerative treatment of Alzheimer's disease (AD). Unfortunately, most proteins cannot be effectively delivered into the brain from the blood stream due to the presence of the blood-brain barrier (BBB). In this study, we delivered BDNF using ADTC5 as BBB modulator (BBBM) into the brains of transgenic APP/PS1 mice, a mouse model for AD.

Noninvasive Brain Delivery and Efficacy of BDNF to Stimulate Neuroregeneration and Suppression of Disease Relapse in EAE Mice.

The number of FDA-approved protein drugs (biologics), such as antibodies, antibody-drug conjugates, hormones, and enzymes, continues to grow at a rapid rate; most of these drugs are used to treat diseases of the peripheral body. Unfortunately, most of these biologics cannot be used to treat brain diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), and brain tumors in a noninvasive manner due to their inability to permeate the blood-brain barrier (BBB). Therefore, there is a need to develop an effective method to deliver protein drugs into the brain.

Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides.

Many proteins can be used to treat brain diseases; however, the presence of the blood-brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 and HAV6 peptides. This study goal was to design new cyclic peptides with N-to-C terminal cyclization for better plasma stability and modulation of the BBB.

Brain Delivery and Brain Deposition of Proteins with Various Sizes.

It is very challenging to develop protein drugs for the treatment of brain diseases; this is due to the difficulty in delivering them into the brain because of the blood-brain barrier (BBB). Thus, alternative delivery methods need further exploration for brain delivery of proteins to diagnose and treat brain diseases. Previously, ADTC5 and HAV6 peptides have been shown to enhance the brain delivery of small- and medium-size molecules across the BBB.

Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors.

The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model.

Methotrexate disposition, anti-folate activity and efficacy in the collagen-induced arthritis mouse model.

Methotrexate (MTX) efficacy in autoimmune arthritis is variable and unpredictable resulting in the need for the identification of biomarkers to guide drug therapy. This study utilizes the collagen-induced arthritis mouse model to investigate erythrocyte MTX disposition and anti-folate activity as biochemical markers of efficacy in autoimmune arthritis. Following induction of arthritis, DBA/1J mice were treated with once-weekly subcutaneous MTX at varying doses over a period of 40 days.

Protein PEGylation for cancer therapy: bench to bedside.

PEGylation is a biochemical modification process of bioactive molecules with polyethylene glycol (PEG), which lends several desirable properties to proteins/peptides, antibodies, and vesicles considered to be used for therapy or genetic modification of cells. However, PEGylation of proteins is a complex process and can be carried out using more than one strategy that depends on the nature of the protein and the desired application. Proteins of interest are covalently conjugated or non-covalently complexed with inert PEG strings.

Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases.

Overexpressed cell-surface receptors are hallmarks of many disease states and are often used as markers for targeting diseased cells over healthy counterparts. Cell adhesion peptides, which are often derived from interacting regions of these receptor-ligand proteins, mimic surfaces of intact proteins and, thus, have been studied as targeting agents for various payloads to certain cell targets for cancers and autoimmune diseases. Because many cytotoxic agents in the free form are often harmful to healthy cells, the use of cell adhesion peptides in targeting their delivery to diseased cells has been studied to potentially reduce required effective doses and associated harmful side-effects.

Peptides and Drug Delivery.

Peptides have been used as drugs to treat various health conditions, and they are also being developed as diagnostic agents. Due to their receptor selectivity, peptides have recently been utilized for drug delivery to target drug molecules to specific types of cells (i.e.