Dataset Information

Structures of SARS-CoV-2 RNA-Binding Proteins and Therapeutic Targets.

ABSTRACT:

Background

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemic has resulted in thousands of infections and deaths worldwide. Several therapies are currently undergoing clinical trials for the treatment of SARS-CoV-2 infection. However, the development of new drugs and the repositioning of existing drugs can only be achieved after the identification of potential therapeutic targets within structures, as this strategy provides the most precise solution for developing treatments for sudden epidemic infectious diseases.

Summary

In the current investigation, crystal and cryo-electron microscopy structures encoded by the SARS-CoV-2 genome were systematically examined for the identification of potential drug targets. These structures include nonstructural proteins (Nsp-9; Nsp-12; and Nsp-15), nucleocapsid (N) proteins, and the main protease (Mpro). Key Message: The structural information reveals the presence of many potential alternative therapeutic targets, primarily involved in interaction between N protein and Nsp3, forming replication-transcription complexes (RTCs) which might be a potential drug target for effective control of current SARS-CoV-2 pandemic. RTCs consist of 16 nonstructural proteins (Nsp1-16) that play the most essential role in the synthesis of viral RNA. Targeting the physical linkage between the envelope and single-stranded positive RNA, a process facilitated by matrix proteins may provide a good alternative strategy. Our current study provides useful information for the development of new lead compounds against SARS-CoV-2 infections.

SUBMITTER: Khan MT

PROVIDER: S-EPMC7900486 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as a regulator of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers; glioblastoma; and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGFβ/SMAD3, MYC, cMET, and others. On the basis of these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis, and development of more aggressive cancer phenotypes, including drug resistance. Although RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising, and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor-profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target. Clin Cancer Res; 23(9); 2143-53. ©2017 AACR.

Project description:Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10-20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5' end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

Dataset Information

Structures of SARS-CoV-2 RNA-Binding Proteins and Therapeutic Targets.

Background

Summary

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