5UOP

CRYSTAL STRUCTURE OF THE PROTOTYPE FOAMY VIRUS INTASOME WITH A 2- PYRIDINONE AMINAL INHIBITOR (COMPOUND 18)

5UOP の概要

• エントリーDOI: 10.2210/pdb5uop/pdb
• 関連するPDBエントリー: 5uoq
• 分子名称: INTEGRASE, NUCLEOTIDE PREPROCESSED PFV DONOR DNA (NON-TRANSFERRED STRAND), NUCLEOTIDE PREPROCESSED PFV DONOR DNA (TRANSFERRED STRAND), ... (9 entities in total)
• 機能のキーワード: dna integration, viral protein, recombination-inhibitor-dna complex, transferase-dna-inhibitor complex, transferase/dna/inhibitor
• 由来する生物種: Human spumaretrovirus (SFVcpz(hu)); 詳細
• 細胞内の位置: Integrase: Virion . Protease/Reverse transcriptase/ribonuclease H: Host nucleus : P14350
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 101397.53

構造登録者

Klein, D.J. (登録日: 2017-02-01, 公開日: 2017-03-29, 最終更新日: 2024-03-06)

主引用文献

Schreier, J.D.,Embrey, M.W.,Raheem, I.T.,Barbe, G.,Campeau, L.C.,Dubost, D.,McCabe Dunn, J.,Grobler, J.,Hartingh, T.J.,Hazuda, D.J.,Klein, D.,Miller, M.D.,Moore, K.P.,Nguyen, N.,Pajkovic, N.,Powell, D.A.,Rada, V.,Sanders, J.M.,Sisko, J.,Steele, T.G.,Wai, J.,Walji, A.,Xu, M.,Coleman, P.J.
Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.
Bioorg. Med. Chem. Lett., 27:2038-2046, 2017

PubMed Abstract: HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

PubMed: 28285916
DOI: 10.1016/j.bmcl.2017.02.039

実験手法

X-RAY DIFFRACTION (2.85 Å)