Current Topics in Medicinal Chemistry - Volume 21, Issue 16, 2021

As a part of the efforts to quickly develop pharmaceutical treatments for COVID-19 through repurposing existing drugs, some researchers around the world have combined the recently released crystal structure of SARS-CoV-2 M^pro in complex with a covalently bonded inhibitor with virtual screening procedures employing molecular docking approaches. In this context, protease inhibitors (PIs) clinically available and currently used to treat infectious diseases, particularly viral ones, are relevant sources of promising drug candidates to inhibit the SARS-CoV-2 M^pro, a key viral enzyme involved in crucial events during its life cycle. In the present perspective, we summarized the published studies showing the promising use of HIV and HCV PIs as potential repurposing drugs against the SARS-CoV-2 M^pro.

Schizophrenia is a serious psychiatric disorder leading to cognitive impairment and has higher rates of morbidity and mortality. There is a need to understand the mechanisms underlying the onset and progression of the disease as the clinical presentation may vary in patients and inadequate knowledge of neurochemical alterations can lead to decreased efficacy in treatment which makes it necessary to identify new potent biomarkers. Identification of biomarkers in schizophrenia offers significant benefits to the well-being of patients, including better prognosis, diagnosis, detection, screening, enhancement in treatment efficacy, prevention of relapse, and better clinical results. Incorporation of advanced technological techniques is necessary to provide an approach for the diagnosis and treatment of psychiatric disorders and to permit specific therapeutic interventions. This review highlights the particulars about the current use and application of various biomarkers such as proteomics, miRNAs, language techniques, antibodies, blood biomarkers, gut microbiota, such as analysis, neuroimaging techniques, and inflammatory biomarkers in effective prognosis, detection, and treatment of schizophrenia and which would contribute as an additional tool for a psychiatrist in cases where an appropriate diagnosis is lacking clarity.

Background: In the past few decades, increasing evidence in the literature has appeared describing the role of the antioxidant defense system and redox signaling in the multifactorial pathophysiology of psychosis. It is of interest to clinicians and researchers alike that abnormalities of the antioxidant defense system are associated with alterations of cellular membranes, immune functions and neurotransmission, all of which have some clinical implications.

Methods: This narrative review summarizes the evidence regarding oxidative stress in the early stages of psychosis. We included 136 peer-reviewed articles published from 2007 to 2020 on PubMed EMBASE, The Cochrane Library and Google Scholar.

Results: Patients affected by psychotic disorders show a decreased level of non-enzymatic antioxidants, an increased level of lipid peroxides, nitric oxides, and a homeostatic imbalance of purine catabolism. In particular, a significantly reduced antioxidant defense has been described in the early onset first episode of psychosis, including reduced levels of glutathione. Also, it has been shown that a decreased basal low-antioxidant capacity correlates with cognitive deficits and negative symptoms, mostly related to glutamate-receptor hypofunction. In addition, atypical antipsychotic drugs seem to show significant antioxidant activity. These factors are critical in order to treat cases of first-onset psychosis effectively.

Conclusion: This systematic review indicates the importance that must be given to anti-oxidant defense systems.

The role of the Galectin-3 (Gal-3) has already been explored in various somatic diseases, considering its engagement in infection, acute and chronic inflammation, and autoimmunity. Additionally, it has been recognized that Gal-3 is included in neuroinflammation and neurodegeneration, so we presented the possibility for its involvement in neuroprogression in schizophrenia. Gal-3 possibly participates in the early life programming of schizophrenia, also in the specific response to viral infections as a “second hit” later in life, and as a part of a unique systemic somatic dysfunction leading to the specific mental changes. In this review, we would like to put all these previous observations of Gal-3 properties in the context of schizophrenia onset, clinical symptoms presentation, frequent somatic comorbid states, and future options for Gal-3 centered treatment in schizophrenia.

The approach towards myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010, 8, 35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity.This bottom- up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

Background: The pharmacological treatment of schizophrenia is currently based on the employment of antipsychotic medications showing an antagonism of dopaminergic and serotoninergic inhibitors. 20-40% of patients are drug-resistant or residually symptomatic in the long-term antipsychotic treatment, and new strategies are needed for improving their functional and cognitive impairment. Methods: This systematic review has summarized evidences from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, and Google Scholar. Results: The possible role of glutamate and its receptors as targets of the antipsychotic mechanism of action has been described. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. Results show an efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA- Receptor antagonist) for cognition and psychopathology. The putative antipsychotic effect of cannabidiol on positive symptoms and cognition will also be discussed. The action on serotoninergic and GABAergic receptors will be considered as a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown to induce improvements in cognitive symptoms in schizophrenia, as well as Erythropoietin. Oxytocin has been reported to have an antipsychotic-like effect; moreover, COX-2 inhibitors lead to a reduction in positive symptoms of psychosis, specifically in the first episode of illness. Conclusion: This narrative report suggests a promising role of new agents in the treatment of Schizophrenia; however, more research is needed to approve their clinical employment.