Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

Akbulut, Ekrem

doi:10.1590/1678-4685-gmb-2021-0404

Cited by 3 publications

(2 citation statements)

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“…[66][67][68][69][70][71][72] The catalytic site of 3CL pro is located at the intersection of domains I and II, which can be divided into mainly five sub-pockets, including S1, S2, S3, S4, and S5 (Figure 2). 36,73 The key facial residues of five sub-pockets are listed in Table S1, whose dimensional chemical environment matches five specific substrate-binding positions. 64,74,75 P1, P2, and P1ʹ positions mainly determine the substrate specificity of 3CL pro , while P4, P3, and P3ʹ boost the recognition and stable binding of substrates.…”

Section: Structural Features and Function Of 3cl Promentioning

confidence: 99%

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

Xiong

Zhu

et al. 2022

MedComm

112

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The main proteases (Mpro), also termed 3‐chymotrypsin‐like proteases (3CLpro), are a class of highly conserved cysteine hydrolases in β‐coronaviruses. Increasing evidence has demonstrated that 3CLpros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus‐caused infectious diseases, including COVID‐19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease Mpro (also known as 3CLpro), as well as recent advances in discovering and developing SARS‐CoV‐2 3CLpro inhibitors. To better understand the characteristics of SARS‐CoV‐2 3CLpro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CLpro inhibitors (including marketed drugs, peptidomimetic, and non‐peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CLpro inhibitors as novel anti‐coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS‐CoV‐2 3CLpro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CLpro inhibitors as novel anti‐coronavirus agents.

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Section: Structural Features and Function Of 3cl Promentioning

confidence: 99%

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

Xiong

Zhu

et al. 2022

MedComm

112

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“…Mutations can cause changes in protein functional properties and protein-protein interactions by triggering changes in protein structure and stability. These changes are the basis of the development mechanism of many diseases ( 17 , 18 , 19 ). It should be kept in mind that the changes caused by mutations will trigger changes not only in the mutant protein but also in other proteins and structures with which it interacts.…”

Section: Introductionmentioning

confidence: 99%

Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism

Çiftçi¹,

Akıncı²,

Akbulut³

et al. 2023

Jcrpe

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Objective: Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups-Kalman syndrome and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing with nexrt generation sequencing (NGS) is required for patients without typical phenotypic findings. The aim was to determine the genetic etiologies of patients with IHH using NGS, including 54 IHH-associated genes, and to present protein homology modeling and protein stability analyzes of the detected variations. Methods: Clinical and demographic data of 16 patients (eight female), aged between 11.6-17.8 years, from different families were assessed. All patients were followed up for a diagnosis of nIHH, had normal cranial imaging, were without anterior pituitary hormone deficiency other than gonadotropins, had no sex chromosome anomaly, had no additional disease, and underwent genetic analysis with NGS between the years 2008-2021. Rare variants were classified according to the variant interpretation framework of the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology. Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed. Results: Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the GNRHR gene, one (6.25%) had a compound heterozygous [likely pathogenic-variants of uncertain significance (VUS)] variant in PROK2 and four (25%) each had a heterozygous (VUS) variant in HESX1 , FGF8 , FLRT3 and DMXL2 . Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH. Conclusion: The frequency of variation detection was similar to the literature. Modelling showed that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.

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Breaking the Chain: Protease Inhibitors as Game Changers in Respiratory Viruses Management

Papaneophytou

2024

IJMS

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Respiratory viral infections (VRTIs) rank among the leading causes of global morbidity and mortality, affecting millions of individuals each year across all age groups. These infections are caused by various pathogens, including rhinoviruses (RVs), adenoviruses (AdVs), and coronaviruses (CoVs), which are particularly prevalent during colder seasons. Although many VRTIs are self-limiting, their frequent recurrence and potential for severe health complications highlight the critical need for effective therapeutic strategies. Viral proteases are crucial for the maturation and replication of viruses, making them promising therapeutic targets. This review explores the pivotal role of viral proteases in the lifecycle of respiratory viruses and the development of protease inhibitors as a strategic response to these infections. Recent advances in antiviral therapy have highlighted the effectiveness of protease inhibitors in curtailing the spread and severity of viral diseases, especially during the ongoing COVID-19 pandemic. It also assesses the current efforts aimed at identifying and developing inhibitors targeting key proteases from major respiratory viruses, including human RVs, AdVs, and (severe acute respiratory syndrome coronavirus-2) SARS-CoV-2. Despite the recent identification of SARS-CoV-2, within the last five years, the scientific community has devoted considerable time and resources to investigate existing drugs and develop new inhibitors targeting the virus’s main protease. However, research efforts in identifying inhibitors of the proteases of RVs and AdVs are limited. Therefore, herein, it is proposed to utilize this knowledge to develop new inhibitors for the proteases of other viruses affecting the respiratory tract or to develop dual inhibitors. Finally, by detailing the mechanisms of action and therapeutic potentials of these inhibitors, this review aims to demonstrate their significant role in transforming the management of respiratory viral diseases and to offer insights into future research directions.

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Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

Cited by 3 publications

References 41 publications

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism

Breaking the Chain: Protease Inhibitors as Game Changers in Respiratory Viruses Management

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Investigation of changes in protein stability and substrate affinity of 3CL-protease of SARS-CoV-2 caused by mutations

Cited by 3 publications

References 41 publications

The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism

Breaking the Chain: Protease Inhibitors as Game Changers in Respiratory Viruses Management

Contact Info

Product

Resources

About

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19