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Publication Abstract from PubMed

In the present study, GRL008, a novel non-peptidic human immunodeficiency virus type-1 (HIV-1) protease inhibitor (PI) and darunavir (DRV), both containing a P2-bis-tetrahydrofuranyl urethane (bis-THF) moiety, exert potent antiviral activity (EC50: 0.029 and 0.002 muM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02), compared to ritonavir (RTV) (EC50: >1.0 muM) and tipranavir (TPV) (EC50: 0.364 muM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected with DRV over 20 passages (HIVDRVRP20) with a 2.6-fold increase in its EC50 (EC50: 0.097 muM) compared to its corresponding EC50 (EC50: 0.038 muM) against wild type HIV-1NL4-3 (HIVWT). In X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone amide-nitrogen/carbonyl-oxygen atoms of conserved active site amino acids, G27, D29, D30 and D30', of HIVA02 protease (PRA02) and wild type PR, in their corresponding crystal structures while TPV lacked H-bonds with G27 and D30' due to absence of polar groups. The P2' thiazolyl moiety of RTV showed two conformations in the crystal structure of PRA02-RTV complex, one of which showed loss of contacts in the S2' binding pocket of PRA02, supporting RTV's compromised antiviral data (EC50: >1 muM). Thus, conserved H-bonding network of P2-bis-THF-containing GRL008 with the backbone of G27, D29, D30 and D30' most likely contribute to its persistently greater antiviral activity against HIVWT, HIVA02, and HIVDRVRP20.

Conserved hydrogen-bonding network of P2 bis-tetrahydrofuran containing HIV-1 protease inhibitors (PI) with protease active site amino acid-backbone aid in their activity against PI-resistant HIV.,Yedidi RS, Garimella H, Aoki M, Aoki H, Desai DV, Chang SB, Davis DA, Fyvie WS, Kaufman JD, Smith DW, Das D, Wingfield PT, Maeda K, Ghosh AK, Mitsuya H Antimicrob Agents Chemother. 2014 Apr 21. PMID:24752271^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.