Exploring new antiviral targets for influenza and COVID-19: Mapping promising hot spots in viral RNA polymerases

Figueiredo-Nunes, Inês; Trigueiro-Louro, João; Rebelo-de-Andrade, Helena

doi:10.1016/j.virol.2022.11.001

“…Instead, each subdomain has some sites that are under strict purifying selection and other sites that are more tolerant to mutation. Similar phenomena were observed in naturally occurring genomes, where conservative and variable residues were distributed relatively evenly across major subdomains (61). These findings highlight the importance of local structures and functional interactions in influenza virus replication.…”

Section: Discussionsupporting

confidence: 76%

Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein

Li,

Arcos,

Sabsay

et al. 2023

Preprint

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The influenza virus polymerase is central to influenza virus evolution. Adaptive mutations within the polymerase are often a prerequisite for efficient spread of novel animal-derived viruses in human populations. The polymerase also determines fidelity, and therefore the rate at which the virus will acquire mutations that lead to host range expansion, drug resistance, or antigenic drift. Despite its importance to viral replication and evolution, our understanding of the mutational effects and associated constraints on the influenza RNA-dependent RNA polymerase (RdRp) is relatively limited. We performed deep mutational scanning of the A/WSN/1933(H1N1) PB1, generating a library of 95.4% of amino acid substitutions at 757 sites. After accuracy filters, we were able to measure replicative fitness for 13,354 (84%) of all possible amino acid substitutions, and 16 were validated by results from pairwise competition assays. Functional and structural constraints were better revealed by individual sites involved in RNA or protein interactions than by major subdomains defined by sequence conservation. Mutational tolerance, as defined by site entropy, was correlated with evolutionary potential, as captured by diversity in available H1N1 sequences. Of 29 beneficial sites, many have either been identified in the natural evolution of PB1 or shown experimentally to have important impacts on replication and adaptation. Accessibility of amino acid substitutions by single nucleotide mutation was a key factor in determining whether mutations appeared in natural PB1 evolution. Our work provides a comprehensive map of mutational effects on a viral RdRp and a valuable resource for subsequent studies of influenza replication and evolution.

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“…Instead, each subdomain has some sites that are under strict purifying selection and other sites that are more tolerant to mutation. Similar phenomena were observed in naturally occurring genomes, where conservative and variable residues were distributed relatively evenly across major subdomains ( 66 ). These findings highlight the importance of local structures and functional interactions in influenza virus replication.…”

Section: Discussionsupporting

confidence: 72%

Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein

Li,

Arcos,

Sabsay

et al. 2023

J Virol

1

0

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The influenza virus polymerase is central to influenza virus evolution. Adaptive mutations within the polymerase are often a prerequisite for efficient spread of novel animal-derived viruses in human populations. The polymerase also determines fidelity and, therefore, the rate at which the virus will acquire mutations that lead to host range expansion, drug resistance, or antigenic drift. Despite its importance to viral replication and evolution, our understanding of the mutational effects and associated constraints on the influenza RNA-dependent RNA polymerase (RdRp) is relatively limited. We performed deep mutational scanning of the A/WSN/1933(H1N1) polymerase basic 1 (PB1), generating a library of 95.4% of amino acid substitutions at 757 sites. After accuracy filters, we were able to measure replicative fitness for 13,354 (84%) of all possible amino acid substitutions, and 13 were validated by results from pairwise competition assays. Functional and structural constraints were better revealed by individual sites involved in RNA or protein interactions than by major subdomains defined by sequence conservation. Mutational tolerance, as defined by site entropy, was correlated with evolutionary potential, as captured by diversity in the available H1N1 sequences. Of the 29 beneficial sites, many have either been identified in the natural evolution of PB1 or shown experimentally to have important impacts on replication and adaptation. Accessibility of amino acid substitutions by single nucleotide mutation was a key factor in determining whether mutations appeared in natural PB1 evolution. Our work provides a comprehensive map of mutational effects on a viral RdRp and a valuable resource for subsequent studies of influenza replication and evolution. IMPORTANCE The influenza virus polymerase is important for adaptation to new hosts and, as a determinant of mutation rate, for the process of adaptation itself. We performed a deep mutational scan of the polymerase basic 1 (PB1) protein to gain insights into the structural and functional constraints on the influenza RNA-dependent RNA polymerase. We find that PB1 is highly constrained at specific sites that are only moderately predicted by the global structure or larger domain. We identified a number of beneficial mutations, many of which have been shown to be functionally important or observed in influenza virus’ natural evolution. Overall, our atlas of PB1 mutations and their fitness impacts serves as an important resource for future studies of influenza replication and evolution.

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“…This protein contains seven motifs [ 291 ]. Among these, motifs A-F are highly protected from RDRP encoded by the virus [ 292 , 293 ]. Motifs J, as an RDRP, are primer-dependent in several viruses.…”

Section: Introductionmentioning

confidence: 99%

Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases

Kakavandi

¹

,

Zare²,

Vaezjalali

³

et al. 2023

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Coronavirus disease 2019 (COVID-19) is caused by a new member of the Coronaviridae family known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are structural and non-structural proteins (NSPs) in the genome of this virus. S, M, H, and E proteins are structural proteins, and NSPs include accessory and replicase proteins. The structural and NSP components of SARS-CoV-2 play an important role in its infectivity, and some of them may be important in the pathogenesis of chronic diseases, including cancer, coagulation disorders, neurodegenerative disorders, and cardiovascular diseases. The SARS-CoV-2 proteins interact with targets such as angiotensin-converting enzyme 2 (ACE2) receptor. In addition, SARS-CoV-2 can stimulate pathological intracellular signaling pathways by triggering transcription factor hypoxia-inducible factor-1 (HIF-1), neuropilin-1 (NRP-1), CD147, and Eph receptors, which play important roles in the progression of neurodegenerative diseases like Alzheimer's disease, epilepsy, and multiple sclerosis, and multiple cancers such as glioblastoma, lung malignancies, and leukemias. Several compounds such as polyphenols, doxazosin, baricitinib, and ruxolitinib could inhibit these interactions. It has been demonstrated that the SARS-CoV-2 spike protein has a stronger affinity for human ACE2 than the spike protein of SARS-CoV, leading the current study to hypothesize that the newly produced variant Omicron receptor-binding domain (RBD) binds to human ACE2 more strongly than the primary strain. SARS and Middle East respiratory syndrome (MERS) viruses against structural and NSPs have become resistant to previous vaccines. Therefore, the review of recent studies and the performance of current vaccines and their effects on COVID-19 and related diseases has become a vital need to deal with the current conditions. This review examines the potential role of these SARS-CoV-2 proteins in the initiation of chronic diseases, and it is anticipated that these proteins could serve as components of an effective vaccine or treatment for COVID-19 and related diseases.

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Exploring new antiviral targets for influenza and COVID-19: Mapping promising hot spots in viral RNA polymerases

Cited by 3 publications

References 64 publications

Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein

Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein

Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein

Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases

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