Hydrophobic C-Terminal Peptide Analog Aß31-41 Protects the Neurons from Aß-Induced Toxicity.

Spontaneous aggregation of amyloid beta (Aß) leads to the formation of neurotoxic senile plaque considered as the most crucial event in Alzheimer's disease (AD) progression. Inhibition or disruption of this deadly aggregate formation is one of the most efficient strategies for the development of potential therapeutics, and extensive research is in progress by various research groups. In this direction, the development of a peptide analogous to that of the native Aß peptide is an attractive strategy. Based on this rationale, ß-sheet breakers were developed from the Aß central hydrophobic core. These peptide derivatives will bind to the full length of the parent Aß and interfere in self-recognition, thereby preventing the folding of the Aß peptide into cross ß-sheet neurotoxic aggregates. However, this approach is effective in the inhibition of fibrillar aggregation, but this strategy is ineffective in the Aß neurotoxic oligomer formation. Therefore, an alternative and efficient approach is to use the Aß peptide analogous to the C-terminal region, which arbitrates fibrillation and oligomerization. Herein, we developed the Aß C-terminal fragment (ACT-1 to ACT-7) for inhibition of oligomerization as well as fibrillar aggregation. Screening of these seven peptides resulted in an efficient anti-Aß peptide aggregative agent (ACT-7), which was evaluated by the ThT assay peptide. The ThT assay reveals complete inhibition and showed significant neuroprotection of PC-12-derived neurons from Aß-induced toxicity and reduced cell apoptosis. Further, analysis using CD and FTIR spectroscopy reveals that the ACT-7 peptide efficiently inhibits the formation of the ß-sheet secondary structure content. HR-TEM microscopic analysis confirmed the inhibition of formation. Therefore, the inhibition of ß-sheet Aß fibrillary aggregation by the protease-stable ACT-7 peptide may provide a beneficial effect on AD treatment to control the Aß aggregates. Finally, we anticipate that our newly designed ACT peptides may also assist as a template molecular scaffold for designing potential anti-AD therapeutics.

Power of Dopamine: Multifunctional Compound Assisted Conversion of the Most Risk Factor into Therapeutics of Alzheimer's Disease.

In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-ß (Aß) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aß-Cu2+ complex as Aß peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aß-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

Discovery of Quinazoline and Quinoline-Based Small Molecules as Utrophin Upregulators via AhR Antagonism for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.

High-Affinity Fluorescent Probes for the Detection of Soluble and Insoluble Aß Deposits in Alzheimer's Disease.

The overproduction and deposition of the amyloid-ß (Aß) aggregates are accountable for the genesis and development of the neurologic disorder Alzheimer's disease (AD). Effective medications and detection agents for AD are still deficient. General challenges for the diagnosis of Aß aggregates in the AD brain are (i) crossing the blood-brain barrier (BBB) and (ii) selectivity to Aß species with (iii) emission maxima in the 500-750 nm region. Thioflavin-T (ThT) is the most used fluorescent probe for imaging Aß fibril aggregates. However, because of the poor BBB crossing (log P = -0.14) and short emission wavelength (482 nm) after binding with Aß fibrils, ThT can be limited to in vitro use only. Herein, we have developed Aß deposit-recognizing fluorescent probes (ARs) with a D-π-A architecture and a longer emission wavelength after binding with Aß species. Among the newly designed probes, AR-14 showed an admirable fluorescence emission (>600 nm) change after binding with soluble Aß oligomers (2.3-fold) and insoluble Aß fibril aggregates (4.5-fold) with high affinities Kd = 24.25 ± 4.10 nM; Ka = (4.123 ± 0.69) × 107 M-1 for fibrils; Kd = 32.58 ± 4.89 nM; and Ka = (3.069 ± 0.46) × 107 M-1 for oligomers with high quantum yield, molecular weight of <500 Da, reasonable log P = 1.77, stability in serum, and nontoxicity, and it can cross the BBB efficiently. The binding affinity of AR-14 toward Aß species is proved by fluorescence binding studies and fluorescent staining of 18-month-old triple-transgenic (3xTg) mouse brain sections. In summary, the fluorescent probe AR-14 is efficient and has an admirable quality for the detection of soluble and insoluble Aß deposits in vitro and in vivo.

Fiction and Facts about BCG Imparting Trained Immunity against COVID-19.

The Bacille Calmette-Guérin or BCG vaccine, the only vaccine available against Mycobacterium tuberculosis can induce a marked Th1 polarization of T-cells, characterized by the antigen-specific secretion of IFN-γ and enhanced antiviral response. A number of studies have supported the concept of protection by non-specific boosting of immunity by BCG and other microbes. BCG is a well-known example of a trained immunity inducer since it imparts 'non-specific heterologous' immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the recent pandemic. SARS-CoV-2 continues to inflict an unabated surge in morbidity and mortality around the world. There is an urgent need to devise and develop alternate strategies to bolster host immunity against the coronavirus disease of 2019 (COVID-19) and its continuously emerging variants. Several vaccines have been developed recently against COVID-19, but the data on their protective efficacy remains doubtful. Therefore, urgent strategies are required to enhance system immunity to adequately defend against newly emerging infections. The concept of trained immunity may play a cardinal role in protection against COVID-19. The ability of trained immunity-based vaccines is to promote heterologous immune responses beyond their specific antigens, which may notably help in defending against an emergency situation such as COVID-19 when the protective ability of vaccines is suspicious. A growing body of evidence points towards the beneficial non-specific boosting of immune responses by BCG or other microbes, which may protect against COVID-19. Clinical trials are underway to consider the efficacy of BCG vaccination against SARS-CoV-2 on healthcare workers and the elderly population. In this review, we will discuss the role of BCG in eliciting trained immunity and the possible limitations and challenges in controlling COVID-19 and future pandemics.