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2018 Fiscal Year Final Research Report

Structural analysis of a reverse transcriptase inhibitor, EFdA, potent against drug-resistant HIV

Research Project

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Project/Area Number 16K08826
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Virology
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

MAEDA KENJI  国立研究開発法人国立国際医療研究センター, その他部局等, 室長 (50758323)

Project Period (FY) 2016-04-01 – 2019-03-31
KeywordsHIV / 逆転写酵素阻害剤 / 薬剤耐性 / 構造解析 / 新薬開発
Outline of Final Research Achievements

EFdA/MK- 8591, a nucleoside reverse transcriptase inhibitor (NRTI), is a potent and promising long-acting anti-HIV-1 agent. EFdA and its derivatives possess a modified 4’-moiety and potently inhibit the replication of HIV-1 strains resistant to existing NRTIs. Here, we report that EFdA and NRTIs with a 4’-ethynyl-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4'-methyl) did not show this activity. Structural analysis indicated that EFdA and 4’-ethynyl-NRTIs (but not other 4’-modified NRTIs), formed strong van der Waals interactions with critical amino acid residues of reverse transcriptase. Such interactions were maintained even in the presence of a broad resistance-endowing M184V substitution, thus potently inhibiting drug-resistant HIV-1 strains. These findings also explain the mechanism for the potency of EFdA and provide insights for further design of anti-HIV-1 therapeutics.

Free Research Field

HIV感染症

Academic Significance and Societal Importance of the Research Achievements

本研究で行われた強力な逆転写酵素阻害剤(EFdA)の薬剤耐性メカニズムに対する構造学的研究から得られた知見は薬剤耐性HIVに対して有効な新規抗HIV薬の設計・開発に寄与するものであり、構造学的エビデンスに基づいた効率的な薬剤開発の有効性を示唆するものである。
さらに本研究で得られた阻害剤のHIV薬剤耐性に関わる構造についてはHIV逆転写酵素(HIV-RT)とB型肝炎ウイルスのHBV-RTに対する阻害剤の親和性の違いにも関連していることが分かってきており、今後各種のRT(およびDNAポリメラーゼ)とその阻害剤に関する構造・活性比較解析研究の進展と新たな治療薬開発が期待される。

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Published: 2020-03-30  

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