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• W1969486078 abstract "ABSTRACT Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis -tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1 LAI and had 50% effective concentrations (EC 50 s) of as low as 0.002 μM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1 NL4-3 variants selected by up to 5 μM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC 50 s of 0.020 to 0.046 μM and potent activities against six multi-PI-resistant clinical HIV-1 (HIV mPI r ) variants with EC 50 s of 0.027 to 0.089 μM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1 NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 μM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 μM [HIV 216-0.16 μM ]), HIV-1 NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC 50 s being 3- to 8-fold-greater than the EC 50 of each drug for HIV-1 NL4-3 . Interestingly, HIV 216-0.16 μM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIV mPI r ." @default.
• W1969486078 created "2016-06-24" @default.
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• W1969486078 date "2010-08-01" @default.
• W1969486078 modified "2023-09-26" @default.
• W1969486078 title "Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3( <i>R</i> ),3a( <i>S</i> ),6a( <i>R</i> )- <i>bis</i> -Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants <i>In Vitro</i>" @default.
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• W1969486078 doi "https://doi.org/10.1128/aac.01766-09" @default.
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