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Antimicrobial Agents and Chemotherapy, April 2008, p. 1337-1344, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01132-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Characterization of a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, A-790742{triangledown}

Tatyana Dekhtyar,* Teresa I. Ng, Liangjun Lu, Sherie Masse, David A. DeGoey, William J. Flosi, David J. Grampovnik, Larry L. Klein, Dale J. Kempf, and Akhteruzzaman Molla

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064

Received 27 August 2007/ Returned for modification 5 October 2007/ Accepted 20 December 2007

A-790742 is a potent human immunodeficiency virus type 1 (HIV-1) protease inhibitor, with 50% effective concentrations ranging from 2 to 7 nM against wild-type HIV-1. The activity of this compound is lowered by approximately sevenfold in the presence of 50% human serum. A-790742 maintained potent antiviral activity against lopinavir-resistant variants generated in vitro as well as against a panel of molecular clones containing proteases derived from HIV-1 patient isolates with multiple protease mutations. During in vitro selection, A-790742 selected two primary mutations (V82L and I84V) along with L23I, L33F, K45I, A71V/A, and V77I in the pNL4-3 background and two other mutations (A71V and V82G) accompanied by M46I and L63P in the HIV-1 RF background. HIV-1 pNL4-3 clones with a single V82L or I84V mutation were phenotypically resistant to A-790742 and ritonavir. Taking these results together, A-790742 displays a favorable anti-HIV-1 profile against both the wild type and a large number of mutants resistant to other protease inhibitors. The selection of the uncommon V82L and V82G mutations in protease by A-790742 suggests the potential for an advantageous resistance profile with this protease inhibitor.

* Corresponding author. Mailing address: 200 Abbott Park Rd., R43H, AP52-N, Abbott Park, IL 60064. Phone: (847) 935-1318. Fax: (847) 938-3403. E-mail: tanya.chernyavskiy{at}abbott.com

{triangledown} Published ahead of print on 22 January 2008.

Antimicrobial Agents and Chemotherapy, April 2008, p. 1337-1344, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01132-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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