Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development

Abstract

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histonelike nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.

Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses

“…Inhibiting the host protein folding machinery has been proposed as a promising broad antiviral strategy [ 55 ] and during recent years, Hsp70 have been validated as a promising antiviral target [ 56 ]. HSP family members possess distinct functions in various steps of RNA and DNA viruses such as supporting CCHFV replication [ 39 ].…”

Genes with 5′ terminal oligopyrimidine tracts preferentially escape global suppression of translation by the SARS-CoV-2 Nsp1 protein

“…In addition, three chaperones-BAG6, HSPA8, and HSP90AB1-were among high-TE genes. These chaperones may play critical roles as cells producing viral protein may require sustained chaperone activity to ensure proper folding (Aviner and Frydman, 2020;Binici and Koch, 2014;Wan et al, 2020). Taken together, NSP1 expression in human cells is associated with a remarkably coherent translational program that differentially sustains the availability of host translation machinery and protein folding capacity.…”

A Bioelectromagnetic Proposal Approaching the Complex Challenges of COVID-19

“…Despite the normal cellular reactions that induce apoptosis, the "hostile behavior" of HSPs disrupts apoptotic processes, blocks the signal pathways that keep infected cells active [274]. HSP70 has a belligerent activity in viral infection with their protective functions, it cooperates with numerous viruses [275], keeping the host cell alive during the virus's replication and exit. The intrinsic mitochondrial pathway of apoptosis in cells infected with SARS-CoV-2 is positively correlated with the induction of viral pathogenesis of apoptosis and virus replication [276] [277].…”

“…We have to apply mEHT in the mild or moderate phase of the disease when the inflammation and cytokine production promote immune activity and do not lead to an emergency cytokine storm condition. Recurrent in the "double-edged sword" phenomenon also characterizes all elements of DAMP, shown for CRT [303] [304] and for HMGB1 [305] and in HSP70 [275]. ATP as an energy source for dynamic changes could also support viral infection through its energy supply function.…”