Current Topics in Medicinal Chemistry - Volume 20, Issue 26, 2020

Embryonic stem cells (ESCs) are stem cells (SCs) that can self-renew and differentiate into a myriad of cell types. The process of developing stemness is determined by signaling molecules that drive stem cells to a specific lineage. For example, ESCs can differentiate into mature cells (e.g., cardiomyocytes) and mature cardiomyocytes can be characterized for cell beating, action potential, and ion channel function. A goal of this Perspective is to show how small molecules can be used to differentiate ESCs into cardiomyocytes and how this can reveal novel aspects of SC biology. This approach can also lead to the discovery of new molecules of use in cardiovascular disease. Human induced pluripotent stem cells (hiPSCs) afford the ability to produce unlimited numbers of normal human cells. The creation of patient-specific hiPSCs provides an opportunity to study cell models of human disease. The second goal is to show that small molecules can stimulate hiPSC commitment to cardiomyocytes. How iPSCs can be used in an approach to discover new molecules of use in cardiovascular disease will also be shown in this study. Adult SCs, including mesenchymal stem cells (MSCs), can likewise participate in self-renewal and multilineage differentiation. MSCs are capable of differentiating into osteoblasts, adipocytes or chondrocytes. A third goal of this Perspective is to describe differentiation of MSCs into chondrogenic and osteogenic lineages. Small molecules can stimulate MSCs to specific cell fate both in vitro and in vivo. In this Perspective, some recent examples of applying small molecules for osteogenic and chondrogenic cell fate determination are summarized. Underlying molecular mechanisms and signaling pathways involved are described. Small molecule-based modulation of stem cells shows insight into cell regulation and potential approaches to therapeutic strategies for MSC-related diseases.

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

Growing concern about neurodegenerative diseases is becoming a global issue. It is estimated that not only will their prevalence increase but also morbidity and health burden will be concerning. Scientists, researchers and clinicians share the responsibility of raising the awareness and knowledge about the restricting and handicapping health restrains related to these diseases. Multiple Sclerosis (MS), as one of the prevalent autoimmune diseases, is characterized by abnormal regulation of the immune system that periodically attacks parts of the nervous system; brain and spinal cord. Symptoms and impairments include weakness, numbness, visual problems, tingling pain that are quietly variable among patients. Amyotrophic Lateral Sclerosis (ALS) is another neurodegenerative disease that is characterized by the degeneration of motor neurons in the brain and spinal cord. Unlike MS, symptoms begin with muscle weakness and progress to affect speech, swallowing and finally breathing. Despite the major differences between MS and ALS, misdiagnosis is still influencing disease prognosis and patient’s quality of life. Diagnosis depends on obtaining a careful history and neurological examination as well as the use of Magnetic Resonance Imaging (MRI), which are considered challenging and depend on the current disease status in individuals. Fortunately, a myriad of treatments is available now for MS. Most of the cases are steroid responsive. Disease modifying therapy is amongst the most important set of treatments. In ALS, few medications that slow down disease progression are present. The aim of this paper is to summarize what has been globally known and practiced about MS and ALS, as they are currently classified as important growing key players among autoimmune diseases. In terms of treatments, it is concluded that special efforts and input should be directed towards repurposing of older drugs and on stem cells trials. As for ALS, it is highlighted that supportive measurements and supplementary treatments remain essentially needed for ALS patients and their families. On the other hand, it is noteworthy to clarify that the patient-doctor communication is relatively a cornerstone in selecting the best treatment for each MS patient.

Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.