An Insight to Heat Shock Protein 90: A Remedy for Multiple Problems.

Heat shock protein 90 (Hsp90) is a chaperone protein that prevents many other proteins from aggregating by folding them in a certain way. Hsp90 consists of three structural domains: N-terminal, middle and C-terminal domains. Hsp90 has many activities in numerous proteins and signaling pathways like chimeric fusion proteins, steroid hormone receptors, tumor suppressor genes, and cell cycle regulatory proteins. The role of Hsp90 is not only in cancer but also in other diseases like COVID-19, leishmaniasis, diabetes, flavi virus, systemic sclerosis, grass carp reovirus, psoriasis, malaria, cardiac fibrosis, and alcohol-related liver diseases. This review is a compilation of the pharmacological profile of Hsp90 inhibitors, problems associated with them, and suggested remedies for the same.

Possible Therapeutic Intervention Strategies for COVID-19 by Manipulating the Cellular Proteostasis Network.

INTRODUCTION: The recent outbreak of coronavirus infection by SARS-CoV-2 that started from the Wuhan Province of China in 2019 has spread to most parts of the world infecting millions of people. Although the case fatality rate of SARS-CoV-2 infection is less than the previous epidemics by other closely related coronaviruses, due to its high infectivity, the total number of SARS-CoV-2 infection-associated disease, called Covid-19, is a matter of global concern. Despite drastic preventive measures, the number of Covid-19 cases are steadily increasing, and the future course of this pandemic is highly unpredictable. The most concerning fact about Covid-19 is the absence of specific and effective preventive or therapeutic agents against the disease. Finding an immediate intervention against Covid-19 is the need of the hour. In this chapter, we have discussed the role of different branches of the cellular proteostasis network, represented by Hsp70-Hsp40 chaperone system, Ubiquitin-Proteasome System (UPS), autophagy, and endoplasmic reticulum-Unfolded Protein Response (ER-UPR) pathway in the pathogenesis of coronavirus infections and in the host antiviral defense mechanisms. RESULTS: Based on scientific literature, we present that pharmacological manipulation of proteostasis network can alter the fate of coronavirus infections and may help to prevent the resulting pathologies like Covid-19.

First Virtual International Congress on Cellular and Organismal Stress Responses, November 5-6, 2020.

Members of the Cell Stress Society International (CSSI), Patricija van Oosten-Hawle (University of Leeds, UK), Mehdi Mollapour (SUNY Upstate Medical University, USA), Andrew Truman (University of North Carolina at Charlotte, USA) organized a new virtual meeting format which took place on November 5-6, 2020. The goal of this congress was to provide an international platform for scientists to exchange data and ideas among the Cell Stress and Chaperones community during the Covid-19 pandemic. Here we will highlight the summary of the meeting and acknowledge those who were honored by the CSSI.

A Roadmap for the Molecular Farming of Viral Glycoprotein Vaccines: Engineering Glycosylation and Glycosylation-Directed Folding.

Immunization with recombinant glycoprotein-based vaccines is a promising approach to induce protective immunity against viruses. However, the complex biosynthetic maturation requirements of these glycoproteins typically necessitate their production in mammalian cells to support their folding and post-translational modification. Despite these clear advantages, the incumbent costs and infrastructure requirements with this approach can be prohibitive in developing countries, and the production scales and timelines may prove limiting when applying these production systems to the control of pandemic viral outbreaks. Plant molecular farming of viral glycoproteins has been suggested as a cheap and rapidly scalable alternative production system, with the potential to perform post-translational modifications that are comparable to mammalian cells. Consequently, plant-produced glycoprotein vaccines for seasonal and pandemic influenza have shown promise in clinical trials, and vaccine candidates against the newly emergent severe acute respiratory syndrome coronavirus-2 have entered into late stage preclinical and clinical testing. However, many other viral glycoproteins accumulate poorly in plants, and are not appropriately processed along the secretory pathway due to differences in the host cellular machinery. Furthermore, plant-derived glycoproteins often contain glycoforms that are antigenically distinct from those present on the native virus, and may also be under-glycosylated in some instances. Recent advances in the field have increased the complexity and yields of biologics that can be produced in plants, and have now enabled the expression of many viral glycoproteins which could not previously be produced in plant systems. In contrast to the empirical optimization that predominated during the early years of molecular farming, the next generation of plant-made products are being produced by developing rational, tailor-made approaches to support their production. This has involved the elimination of plant-specific glycoforms and the introduction into plants of elements of the biosynthetic machinery from different expression hosts. These approaches have resulted in the production of mammalian N-linked glycans and the formation of O-glycan moieties in planta. More recently, plant molecular engineering approaches have also been applied to improve the glycan occupancy of proteins which are not appropriately glycosylated, and to support the folding and processing of viral glycoproteins where the cellular machinery differs from the usual expression host of the protein. Here we highlight recent achievements and remaining challenges in glycoengineering and the engineering of glycosylation-directed folding pathways in plants, and discuss how these can be applied to produce recombinant viral glycoproteins vaccines.

The Role of Molecular Chaperones in Virus Infection and Implications for Understanding and Treating COVID-19.

The COVID-19 pandemic made imperative the search for means to end it, which requires a knowledge of the mechanisms underpinning the multiplication and spread of its cause, the coronavirus SARS-CoV-2. Many viruses use members of the hosts' chaperoning system to infect the target cells, replicate, and spread, and here we present illustrative examples. Unfortunately, the role of chaperones in the SARS-CoV-2 cycle is still poorly understood. In this review, we examine the interactions of various coronaviruses during their infectious cycle with chaperones in search of information useful for future research on SARS-CoV-2. We also call attention to the possible role of molecular mimicry in the development of autoimmunity and its widespread pathogenic impact in COVID-19 patients. Viral proteins share highly antigenic epitopes with human chaperones, eliciting anti-viral antibodies that crossreact with the chaperones. Both, the critical functions of chaperones in the infectious cycle of viruses and the possible role of these molecules in COVID-19 autoimmune phenomena, make clear that molecular chaperones are promising candidates for the development of antiviral strategies. These could consist of inhibiting-blocking those chaperones that are necessary for the infectious viral cycle, or those that act as autoantigens in the autoimmune reactions causing generalized destructive effects on human tissues.

Human molecular chaperones share with SARS-CoV-2 antigenic epitopes potentially capable of eliciting autoimmunity against endothelial cells: possible role of molecular mimicry in COVID-19.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), the cause of COVID-19 disease, has the potential to elicit autoimmunity because mimicry of human molecular chaperones by viral proteins. We compared viral proteins with human molecular chaperones, many of which are heat shock proteins, to determine if they share amino acid-sequence segments with immunogenic-antigenic potential, which can elicit cross-reactive antibodies and effector immune cells with the capacity to damage-destroy human cells by a mechanism of autoimmunity. We identified the chaperones that can putatively participate in molecular mimicry phenomena after SARS-CoV-2 infection, focusing on those for which endothelial cell plasma-cell membrane localization has already been demonstrated. We also postulate that post-translational modifications, induced by physical (shear) and chemical (metabolic) stress caused respectively by the risk factors hypertension and diabetes, might have a role in determining plasma-cell membrane localization and, in turn, autoimmune-induced endothelial damage.

Does SARS-CoV-2 Trigger Stress-InducedAutoimmunity by Molecular Mimicry? A Hypothesis.

Viruses can generate molecular mimicry phenomena within their hosts. Why shouldsevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not be considered one of these?Information in this short review suggests that it might be so and, thus, encourages research aimingat testing this possibility. We propose, as a working hypothesis, that the virus induces antibodiesand that some of them crossreact with host's antigens, thus eliciting autoimmune phenomena withdevasting consequences in various tissues and organs. If confirmed, by in vitro and in vivo tests,this could drive researchers to find effective treatments against the virus.