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Last update 23 Jan 2025

PA protein

Last update 23 Jan 2025

Basic Info

Synonyms-

Introduction

Plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits. The complex transcribes viral mRNAs by using a unique mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. These short capped RNAs are then used as primers for viral mRNAs. The PB2 subunit is responsible for the binding of the 5' cap of cellular pre-mRNAs which are subsequently cleaved after 10-13 nucleotides by the PA subunit that carries the endonuclease activity.

Drugs associated with PA protein

ZX-7101A

Target

PA protein x RdRp

Mechanism

PA protein inhibitors [+1]

Active Org.

Nanjing Zenshine Pharmaceuticals Co., Ltd. [+1]

Originator Org.

Nanjing Zenshine Pharmaceuticals Co., Ltd.

Active Indication

Influenza, Human [+1]

Inactive Indication-

Drug Highest PhaseNDA/BLA

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GP-681

Target

PA protein

Mechanism

PA protein inhibitors

Active Org.

2Y-Biopharma [+3]

Originator Org.

Ginkgo Pharmaceutical (Suzhou) Co., Ltd.

Active Indication

Influenza, Human [+2]

Inactive Indication-

Drug Highest PhaseNDA/BLA

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ADC-189

Target

CEN x PA protein

Mechanism

CEN inhibitors [+1]

Active Org.

Jiaxing'an Dikang Biotechnology Co., Ltd. [+1]

Originator Org.

Jiaxing'an Dikang Biotechnology Co., Ltd.

Active Indication

Influenza A virus infection [+2]

Inactive Indication-

Drug Highest PhasePhase 3

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PA protein

CTR20244595

/ RecruitingPhase 1

在中国健康受试者空腹状态下单次口服GP681干混悬剂（规格：20mg）及GP681片（规格：20mg）的生物利用度研究

[Translation] Study on the bioavailability of GP681 dry suspension (specification: 20 mg) and GP681 tablets (specification: 20 mg) after a single oral administration in Chinese healthy subjects under fasting state

主要研究目的评价中国健康男性受试者单次口服受试制剂GP681干混悬剂（规格：20mg/袋，生产厂家：江西科睿药业有限公司）及参比制剂GP681片（规格：20mg/片，生产厂家：江西科睿药业有限公司）后的相对生物利用度和药代动力学特征。次要研究目的 1）评价受试制剂GP681干混悬剂（规格：20mg/袋）及参比制剂GP681片（规格：20mg/片）在中国健康男性受试者中单次口服给药的安全性； 2）评价受试者服用受试制剂GP681干混悬剂后的口感（适口性）。

[Translation]

Main study objectives To evaluate the relative bioavailability and pharmacokinetic characteristics of the test preparation GP681 dry suspension (specification: 20 mg/bag, manufacturer: Jiangxi Kerui Pharmaceutical Co., Ltd.) and the reference preparation GP681 tablets (specification: 20 mg/tablet, manufacturer: Jiangxi Kerui Pharmaceutical Co., Ltd.) after a single oral administration in healthy Chinese male subjects. Secondary study objectives 1) To evaluate the safety of single oral administration of the test preparation GP681 dry suspension (specification: 20 mg/bag) and the reference preparation GP681 tablets (specification: 20 mg/tablet) in healthy Chinese male subjects; 2) To evaluate the taste (palatability) of the subjects after taking the test preparation GP681 dry suspension.

Start Date12 Dec 2024

Sponsor / Collaborator

Jiangxi Kerui Pharmaceutical Co., Ltd

[+1]

NCT06574503

/ RecruitingPhase 3

A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled, Clinical Efficacy and Safety Study of GP681 Tablets for Post-exposure Prophylaxis Against Influenza in Adults and Adolescents

Index patients who are infected with influenza virus (Q-PCR positive) can be treated with anti-influenza drugs if their influenza symptoms onset was within 48 hours of screening. Their eligible households will be randomized to either GP681 tablets or placebo if at least 1 household contacts have not received influenza vaccine with 6 months of screening and if all household contacts screen negative for influenza infection. The main endpoints are assessed based on multiple respiratory swabs, obtained from household contacts up to Day 10, and through the assessment of symptoms.

Start Date01 Dec 2024

Sponsor / Collaborator

Jiangxi Qingfeng Pharmaceutical Co. Ltd.

CTR20243107

/ RecruitingPhase 3

GP681片用于成人及青少年流感暴露后预防的有效性及安全性的多中心、随机、双盲、安慰剂对照的Ⅲ期临床研究

[Translation] A multicenter, randomized, double-blind, placebo-controlled phase III clinical study on the efficacy and safety of GP681 tablets for post-exposure prevention of influenza in adults and adolescents

主要研究目的：评价口服单剂量的GP681片与安慰剂相比在流感患者（指示病例）的家庭成员（家庭接触者）流感暴露后预防的有效性。次要研究目的： 1）通过其他次要终点指标评估口服单剂量的GP681片与安慰剂相比在家庭接触者流感暴露后预防的有效性； 2）评价口服单剂量的GP681片与安慰剂相比在家庭接触者流感暴露后预防的安全性。

[Translation]

Main study objectives: To evaluate the effectiveness of a single oral dose of GP681 tablets compared with placebo in the prevention of influenza exposure in family members (household contacts) of influenza patients (index cases). Secondary study objectives: 1) To evaluate the effectiveness of a single oral dose of GP681 tablets compared with placebo in the prevention of influenza exposure in household contacts through other secondary endpoints; 2) To evaluate the safety of a single oral dose of GP681 tablets compared with placebo in the prevention of influenza exposure in household contacts.

Start Date01 Dec 2024

Sponsor / Collaborator

Jiangxi Kerui Pharmaceutical Co., Ltd

[+1]

100 Clinical Results associated with PA protein

100 Translational Medicine associated with PA protein

0 Patents (Medical) associated with PA protein

198

Literatures (Medical) associated with PA protein

31 Dec 2024·RNA Biology

WDR33 alternative polyadenylation is dependent on stochastic poly(a) site usage and splicing efficiencies

Article

Author: Liu, Lizhi ; Seimiya, Takahiro ; Manley, James L.

Transcripts from the human WDR33 gene, which encodes a central component of the mRNA polyadenylation (PA) machinery, are subject to alternative polyadenylation (APA) within promoter-proximal introns/exons. This APA, which itself involves usage of multiple PA sites, results in the production of two non-canonical protein isoforms, V2 and V3, that are functionally completely unrelated to the full-length protein, with roles in innate immunity. The mechanism and regulation of WDR33 APA are unclear. Here, we report that levels of the PA factor CFIm25 modulate V2 and V3 expression, and that PA site usage of both V2 and V3 varies in distinct immune responses. Using newly developed assays to measure splicing and PA site strength, we show that splicing of V2-associated intron 6 is inefficient, allowing V2 to be produced using weak PA sites. Usage of V3's strong PA sites, on the other hand, is relatively low, reflecting the high efficiency of intron 7 splicing coupled with dependency on usage of an alternative 3' splice site within the intron. Overall, our findings demonstrate that usage of WDR33 alternative PA sites is stochastic, dependent on a complex interplay between splicing and PA, and thus provide new insights into mechanisms underlying APA.

01 Dec 2024·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Architecture and function of yeast phosphatidate phosphatase Pah1 domains/regions

Review

Author: Carman, George M ; Stukey, Geordan J ; Han, Gil-Soo

Phosphatidate (PA) phosphatase, which catalyzes the Mg²⁺-dependent dephosphorylation of PA to produce diacylglycerol, provides a direct precursor for the synthesis of the storage lipid triacylglycerol and the membrane phospholipids phosphatidylcholine and phosphatidylethanolamine. The enzyme controlling the key phospholipid PA also plays a crucial role in diverse aspects of lipid metabolism and cell physiology. PA phosphatase is a peripheral membrane enzyme that is composed of multiple domains/regions required for its catalytic function and subcellular localization. In this review, we discuss the domains/regions of PA phosphatase from the yeast Saccharomyces cerevisiae with reference to the homologous enzyme from mammalian cells.

22 Oct 2024·Journal of Virology

Two amino acid residues in the N-terminal region of the polymerase acidic protein determine the virulence of Eurasian avian-like H1N1 swine influenza viruses in mice

Article

Author: Xu, Chengzhi ; Yang, Huanliang ; Chen, Yan ; Qiao, Chuanling ; Zhang, Naixin ; Chen, Hualan ; Wu, Yunpu ; Liu, Liling ; Wan, Yunfei ; Meng, Fei ; Yang, Yuying

ABSTRACT Reassortant Eurasian avian-like H1N1 (rEA H1N1) viruses carrying the internal genes of H1N1/2009 virus have been circulating in pigs for more than 10 years and have caused sporadic human infections. The enhanced virulence phenotype of the rEA H1N1 viruses highlights potential risks to public health. However, the molecular mechanism underlying the viral pathogenicity of the currently circulating rEA H1N1 viruses remains unclear. In this study, we found that two naturally isolated rEA H1N1 swine influenza viruses, A/swine/Liaoning/FX38/2017 (FX38) and A/swine/Liaoning/SY72/2018 (SY72), possessed similar genetic characteristics but exhibited significantly different pathogenicity in a mouse model. Using reverse genetics, we demonstrated that amino acid mutations at positions 100 and 122 in the polymerase acidic (PA) protein had individual and synergistic effects on the polymerase activity and viral replication capacity in vitro , as well as the viral pathogenicity in mice. Furthermore, we revealed that amino acid residue 100 in PA influenced the transcription of viral RNA (vRNA) by altering the endonuclease activity, and amino acid residue 122 affected the synthesis of complementary RNA and messenger RNA by altering the RNA-binding ability and endonuclease activity of the PA protein. Taken together, we identified that two naturally occurring amino acid mutations in PA derived from H1N1/2009 virus are crucial determinants of the virulence of rEA H1N1 viruses and revealed the differential mechanism by which these two mutations affect the transcription and replication of vRNA. These findings will extend our understanding of the roles of PA in the virulence of influenza A viruses. IMPORTANCEMultiple genetic determinants are involved in the virulence of influenza A viruses. In this study, we identified two naturally occurring amino acid mutations, located at residues 100 and 122 in the polymerase acidic (PA) protein, which are associated with viral polymerase activity, replication competence, and pathogenicity in mice. In particular, we clarified the specific mechanism by which the two residues play an important role in viral transcription and replication. These findings will help to improve understanding the functions of amino acid residues in the N-terminal region of the PA protein involved in the pathogenicity of influenza A viruses.

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PA protein

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