A Snake Venom Peptide and Its Derivatives Prevent Aβ Aggregation and Eliminate Toxic Aβ Aggregates .

Over a century has passed since Alois Alzheimer first described Alzheimer's disease (AD), and since then, researchers have made significant strides in understanding its pathology. One key feature of AD is the presence of amyloid-β (Aβ) peptides, which form amyloid plaques, and therefore, it is a primary target for treatment studies. Naturally occurring peptides have garnered attention for their potential pharmacological benefits, particularly in the central nervous system.

Tau protein aggregation associated with SARS-CoV-2 main protease.

The primary function of virus proteases is the proteolytic processing of the viral polyprotein. These enzymes can also cleave host cell proteins, which is important for viral pathogenicity, modulation of cellular processes, viral replication, the defeat of antiviral responses and modulation of the immune response. It is known that COVID-19 can influence multiple tissues or organs and that infection can damage the functionality of the brain in multiple ways.

The Importance of Epigallocatechin as a Scaffold for Drug Development against Flaviviruses.

Arboviruses such as Dengue, yellow fever, West Nile, and Zika are flaviviruses vector-borne RNA viruses transmitted biologically among vertebrate hosts by blood-taking vectors. Many flaviviruses are associated with neurological, viscerotropic, and hemorrhagic diseases, posing significant health and socioeconomic concerns as they adapt to new environments. Licensed drugs against them are currently unavailable, so searching for effective antiviral molecules is still necessary.

Evaluation of the F-labeled analog of the therapeutic all-D-enantiomeric peptide RD2 for amyloid β imaging.

Positron emission tomography (PET) imaging with radiotracers that bind to fibrillary amyloid β (Aβ) deposits is an important tool for the diagnosis of Alzheimer's disease (AD) and for the recruitment of patients into clinical trials. However, it has been suggested that rather than the fibrillary Aβ deposits, it is smaller, soluble Aβ aggregates that exert a neurotoxic effect and trigger AD pathogenesis. The aim of the current study is to develop a PET probe that is capable of detecting small aggregates and soluble Aβ oligomers for improved diagnosis and therapy monitoring.

Stabilization of Monomeric Tau Protein by All D-Enantiomeric Peptide Ligands as Therapeutic Strategy for Alzheimer's Disease and Other Tauopathies.

Alzheimer's disease and other tauopathies are the world's leading causes of dementia and memory loss. These diseases are thought to be caused by the misfolding and aggregation of the intracellular tau protein, ultimately leading to neurodegeneration. The tau protein is involved in a multitude of different neurodegenerative diseases.

Discovery of All-d-Peptide Inhibitors of SARS-CoV-2 3C-like Protease.

During the replication process of SARS-CoV-2, the main protease of the virus [3-chymotrypsin-like protease (3CL)] plays a pivotal role and is essential for the life cycle of the pathogen. Numerous studies have been conducted so far, which have confirmed 3CL as an attractive drug target to combat COVID-19. We describe a novel and efficient next-generation sequencing (NGS) supported phage display selection strategy for the identification of a set of SARS-CoV-2 3CL targeting peptide ligands that inhibit the 3CL protease, in a competitive or noncompetitive mode, in the low μM range.

A So-Far Overlooked Secondary Conformation State in the Binding Mode of SARS-CoV-2 Spike Protein to Human ACE2 and Its Conversion Rate Are Crucial for Estimating Infectivity Efficacy of the Underlying Virus Variant.

Since its outbreak in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread with high transmission efficiency across the world, putting health care as well as economic systems under pressure. During the course of the pandemic, the originally identified SARS-CoV-2 variant has been multiple times replaced by various mutant versions, which showed enhanced fitness due to increased infection and transmission rates. In order to find an explanation for why SARS-CoV-2 and its emerging mutated versions showed enhanced transmission efficiency compared with SARS-CoV (2002), an enhanced binding affinity of the spike protein to human angiotensin converting enzyme 2 (hACE2) has been proposed by crystal structure analysis and was identified in cell culture models.

Design of D-Amino Acids SARS-CoV-2 Main Protease Inhibitors Using the Cationic Peptide from Rattlesnake Venom as a Scaffold.

The C30 endopeptidase (3C-like protease; 3CL) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and, hence, is a promising drug target. Molecules isolated from animals, insects, plants, or microorganisms can serve as a scaffold for the design of novel biopharmaceutical products. Crotamine, a small cationic peptide from the venom of the rattlesnake , has been the focus of many studies since it exhibits activities such as analgesic, in vitro antibacterial, and hemolytic activities.

Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo.

Parkinson's disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD.

Histamine H receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation.

Alzheimeŕs disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H receptor (HR).

Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1 Transgenic Mice.

Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1 mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1 mice.

In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer's Disease.

Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression of Alzheimer's disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials.

The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CL In Vitro.

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude.

Oral absorption enhancement of the amyloid-β oligomer eliminating compound RD2 by conjugation with folic acid.

Amyloid-β (Aβ) plays a central role in the development and progression of Alzheimer's disease (AD) with Aβ oligomers representing the most toxic species. The all-d-enantiomeric peptide RD2, which recently successfully completed clinical phase I, specifically eliminates Aβ oligomers in vitro as well as in vivo and improves cognitive deficits in various transgenic AD mouse models even after oral administration. To further enhance the oral absorption of RD2, folic acid has been conjugated to the d-peptide promoting an endocytosis-mediated uptake via a folate receptor located in the intestine.

Toward the Mode of Action of the Clinical Stage All-d-Enantiomeric Peptide RD2 on Aβ42 Aggregation.

The aggregation of amyloid-β (Aβ) into oligomers and fibrillary structures is critical for the pathogenesis of Alzheimer's disease (AD). Recently, research effort has been focused on developing novel agents that can preferentially suppress Aβ oligomer mediated toxicities, for example, by directly targeting these toxic assemblies. The compound RD2 has been developed and optimized for Aβ42 monomer binding and stabilization of the monomer in its native intrinsically disordered conformation.

Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers.

Alzheimer's disease (AD) is a neurodegenerative disorder leading to dementia. Aggregation of the amyloid-β peptide (Aβ) plays an important role in the disease, with Aβ oligomers representing the most toxic species. Previously, we have developed the Aβ oligomer eliminating therapeutic compound RD2 consisting solely of D-enantiomeric amino acid residues.

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease.

Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates.