SARS-CoV-2, Hypoxia, and Calcium Signaling: The Consequences and Therapeutic Options.

Currently, COVID-19 has created difficulties in understanding the pathological mechanisms and therapeutic options for treatment. COVID-19 patients have shown to be hypoxic, and hypoxia causes alteration of the cell calcium dynamics, which leads to alterations in many signal transduction pathways and gene expression. Also, both viruses and hypoxia directly alter many pathological and biochemical pathways, such as inflammation, cytokine signaling, glycolysis, and calcium signaling. Therefore, understanding of these cellular events would be useful in finding therapeutic options.

Recent advances in drug discovery for diabetic kidney disease.

INTRODUCTION: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD), and 40% of patients with diabetes develop DKD. Although some pathophysiological mechanisms and drug targets of DKD have been described, the effectiveness or clinical usefulness of such treatment has not been well validated. Therefore, searching for new targets and potential therapeutic candidates has become an emerging research area. AREAS COVERED: The pathophysiological mechanisms, new drug targets and potential therapeutic compounds for DKD are addressed in this review. EXPERT OPINION: Although preclinical and clinical evidence has shown some positive results for controlling DKD progression, treatment regimens have not been well developed to reduce the mortality in patients with DKD globally. Therefore, the discovery of new therapeutic targets and effective target-based drugs to achieve better and safe treatment are urgently required. Preclinical screening and clinical trials for such drugs are needed.

Dipeptidyl Peptidase-4: A Potential Therapeutic Target in Diabetic Kidney Disease with SARS-CoV-2 Infection.

Dipeptidyl peptidase-4 (DPP-4) is expressed ubiquitously in many tissues, including kidney, respiratory tract, and immune cells. Human DPP-4 has been identified as a functional receptor for the spike glycoprotein of the Middle East respiratory syndrome coronavirus. A large interface has been predicted in the docking of DPP-4/SARS-CoV-2 spike protein. Globally, 40% of diabetic patients develop diabetic kidney disease (DKD), a leading cause of end-stage renal disease. DPP-4 inhibitors possess anti-inflammatory properties which suggest their potential implication in DKD and SARS-CoV-2 immunopathogenesis.

CNS Penetration Ability: A Critical Factor for Drugs in the Treatment of SARS-CoV-2 Brain Infection.

Now, it has been evidenced that Covid19 (SARS-CoV-2) infects the brain tissues. Along with this, a challenge has been raised for research professionals to find effective drugs for its treatment since the recent spread of this virus from Wuhan, China. Targeting the treatment of brain infection, it has also been a challenge that the clinical drug should have good CNS penetration ability to cross the blood-brain barrier.

Calcium Channel Blockers: A Possible Potential Therapeutic Strategy for the Treatment of Alzheimer's Dementia Patients with SARS-CoV-2 Infection.

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aß) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aß is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.

Investigation of Molecular Properties of Antiretroviral Agents to Enhance CNS Penetration Abilities for the Treatment of Cognitive Impairment in HIV-Associated Neurocognitive Disorder.

HIV-associated neurocognitive disorder (HAND) can be represented by neurological and neuropathological abnormalities with a consequence of motor and cognitive loss. It has become a critical unmet medical need for infected people, and the number continues to rise every year. Pathological investigations have revealed its occurrence due to the release of free radicals from the HIV infected microglia and macrophages. So far, no effective clinical trials have been conducted for its treatment other than the use of some antiretroviral therapies which have failed to show good results due to poor CNS penetration and hence low CNS distribution. This collective information from the updated literature reports motivated us to share the idea of conjugated products of antiretroviral agents and antioxidants leading to better brain penetration abilities due to higher log p values, higher molecular weight and possibly low toxicity and better neuroprotective action. In this Viewpoint, we have attempted to analyze the chemical and pharmacological classes of antiretroviral agents (ARAs) and their clinical failures for the treatment of cognitive dysfunction due to HIV infection. As the causes of clinical insufficiency of antiretroviral agents and neuropathological mechanisms of HAND have been well established, it would be a good opportunity for medicinal chemists to develop new potential antiretroviral agents or to improve their molecular properties for better therapeutic implications. Furthermore, in silico based molecular properties have been investigated correlating them to the brain penetration abilities.

Exploration of [2 + 2 + 2] cyclotrimerisation methodology to prepare tetrahydroisoquinoline-based compounds with potential aldo-keto reductase 1C3 target affinity.

Tetrahydroisoquinoline (THIQ) is a key structural component in many biologically active molecules including natural products and synthetic pharmaceuticals. Here, we report on the use of transition-metal mediated [2 + 2 + 2] cyclotrimerisation of alkynes to generate tricyclic THIQs with potential to selectively inhibit AKR1C3.

Design and synthesis of newer potential 4-(N-acetylamino)phenol derived piperazine derivatives as potential cognition enhancers.

A series of novel hybrids has been designed, synthesized and evaluated for cognition enhancing activities through the inhibition of acetylcholinesterase (AChE) and by passive avoidance mouse model. All the compounds showed excellent AChE inhibition activities and potentially reversed the scopolamine induced memory deficit. Enzyme kinetic and molecular docking studies have confirmed their dual binding affinity and mixed type inhibition. Among them, compounds 1b and 2d displayed excellent IC50 values of 1.66µM and 0.49µM and competitive inhibitor constant Ki 43.66µM and 4.10µM respectively. Ex vivo study confirmed their CNS penetration and brain AChE inhibition abilities. Furthermore, 1b and 2d showed significant antiamnesic activity at a dose of 1.0mg/kg as compared to the reference compounds piracetam and rivastigmine. The results indicate that these two compounds emerged to be developed as cognition enhancers worthy of future pursuit.

The discovery and development of new potential antioxidant agents for the treatment of neurodegenerative diseases.

INTRODUCTION: Several neurodegenerative disorders (NDs) including Alzheimer's and Huntington's diseases have had associations with the oxidative process and free radical damage. Consequently, in past decades, several natural and synthetic antioxidants have been assessed as therapeutic agents but have shown limitations in bioavailability, metabolic susceptibility and permeability to the blood brain barrier. Given these issues, medicinal chemists are hard at work to modify/improve the chemical structures of these antioxidants, thereby improving their efficacy. AREAS COVERED: In this review, the authors critically analyze several biological mechanisms involved in the generation of free radicals. Additionally, they analyze free radicals' role in the generation of oxidative stress and in the progression of many NDs. Further, the authors review a collection of natural and synthetic antioxidants, their role as free radical scavengers along with their mechanisms of action and their potential for preventing neurodegenerative diseases. EXPERT OPINION: So far, preclinical studies on several antioxidants have shown promise for treating NDs, despite their limitations. The authors do highlight the lack of the adequate animal models for preclinical assessment and this does hinder further progression into clinical trials. Further studies are necessary to fully investigate the potential of these antioxidants as ND therapeutic options.