6UM8

HIV Integrase in complex with Compound-14

6UM8 の概要

• エントリーDOI: 10.2210/pdb6um8/pdb
• 分子名称: Integrase, PENTAETHYLENE GLYCOL, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: dna integration, aids, rnaseh, ledgf, endonuclease, hiv-1 integrase, transferase, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38992.06

構造登録者

Khan, J.A.,Kish, K. (登録日: 2019-10-09, 公開日: 2020-03-04, 最終更新日: 2023-10-11)

主引用文献

Li, G.,Meanwell, N.A.,Krystal, M.R.,Langley, D.R.,Naidu, B.N.,Sivaprakasam, P.,Lewis, H.,Kish, K.,Khan, J.A.,Ng, A.,Trainor, G.L.,Cianci, C.,Dicker, I.B.,Walker, M.A.,Lin, Z.,Protack, T.,Discotto, L.,Jenkins, S.,Gerritz, S.W.,Pendri, A.
Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.
J.Med.Chem., 63:2620-2637, 2020

PubMed Abstract: The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine , which was optimized at the 2- and 7-positions to afford and as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

PubMed: 32081010
DOI: 10.1021/acs.jmedchem.9b01681

実験手法

X-RAY DIFFRACTION (2.33 Å)