Understanding the interactability of chikungunya virus proteins via molecular recognition feature analysis

Singh

International Journal of Biological Macromolecules

et al. 2020

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a b s t r a c tRotavirus is a major cause of severe acute gastroenteritis in the infants and young children. The past decade has evidenced the role of intrinsically disordered proteins/regions (IDPs)/(IDPRs) in viral and other diseases. In general, (IDPs)/(IDPRs) are considered as dynamic conformational ensembles that devoid of a specific 3D structure, being associated with various important biological phenomena. Viruses utilize IDPs/IDPRs to survive in harsh environments, to evade the host immune system, and to highjack and manipulate host cellular proteins. The role of IDPs/IDPRs in Rotavirus biology and pathogenicity are not assessed so far, therefore, we have designed this study to deeply look at the penetrance of intrinsic disorder in rotavirus proteome consisting 12 proteins encoded by 11 segments of viral genome. Also, for all human rotaviral proteins, we have deciphered molecular recognition features (MoRFs), which are disorder based binding sites in proteins. Our study shows the wide spread of intrinsic disorder in several rotavirus proteins, primarily the nonstructural proteins NSP3, NSP4, and NSP5 that are involved in viral replication, translation, viroplasm formation and/or maturation. This study may serve as a primer for understanding the role of IDPs/MoRFs in rotavirus biology, design of alternative therapeutic strategies, and development of disorder-based drugs.

Section: Introductionmentioning

confidence: 99%

Understanding the penetrance of intrinsic protein disorder in rotavirus proteome

Singh

International Journal of Biological Macromolecules

et al. 2020

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“…These regions were predicted using four different web servers, MoRFCHiBi_Web [87], ANCHOR [88], MoRFpred [89], and DISOPRED3 [90]. Each predictor uses a different data sets and ANN-based models for prediction, which are described in our MoRF-based studies on Zika virus, Chikungunya virus, Rotavirus, SARS-CoV-2 proteomes, and Alzheimer's-disease-associated amyloid cascade signaling proteins [56,83,84,91,92]. Along with these, another web-based predictor, D2P2 [93] has also been used, which predicts disordered regions as well as motifs in proteins.…”

Section: Molecular Recognition Features (Morfs) Predictionmentioning

confidence: 99%

Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

et al. 2020

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The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

Expert Opinion on Drug Discovery

“…This reality is accompanied by the lack of information on how the viral proteins are interacting with each other and with cellular components, complexes that are crucial for the functional replicative complex (RC). It has recently been reported that CHIKV proteins are characterized by the presence of disordered-based protein-protein interactions (MoRFs) that may help to clarify how protein-protein interactions occur in CHIKV replicative cycle [101]. Probably the lack of information of this interplay also helps to understand why the development of target-based assays has been so difficult, and the only ones reported have been summarized in section 3.3.…”

Section: Expert Opinionmentioning

confidence: 99%

Chikungunya virus drug discovery: still a long way to go?

Pérez‐Pérez

Priego

2019

Introduction: Chikungunya virus (CHIKV) is the etiological agent of a (re)emerging arbovirus infection, chikungunya fever (CHIKF), that represents a serious health problem worldwide for which no antivirals are available. Areas covered: This review covers the efforts performed so far to identify and optimize small molecules that could be useful as antivirals for CHIKV infection, including drug repositioning, phenotypic screening, target-based screening and structure-based design. This is accompanied by a brief presentation of the replicative cycle of the virus and the role of the viral proteins in CHIKV replication. Expert opinion: In the last decade, and particularly since CHIKV reached the Americas, significant efforts have been made to identify compounds that effectively inhibit CHIKV replication. Unfortunately, these efforts have not led to a clinical candidate. For the years to come, more basic research is required to allow a better understanding of the interplay of the viral proteins among them and with cellular components. Structural information is missing for most of the targets so that structure-based drug design, a strategy that has provided good results in other antiviral fields, has been scarcely applied to this alphavirus.