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Antimicrobial Agents and Chemotherapy, February 2006, p. 625-631, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.625-631.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection

Z. Gu,1 B. Allard,1 J. M. de Muys,1 J. Lippens,1 R. F. Rando,1 N. Nguyen-Ba,1 C. Ren,1 P. McKenna,2 D. L. Taylor,3 and R. C. Bethell1*

Shire Biochem, Inc., Laval, Québec, Canada,1 Virco BVBA, Mechelen, Belgium,2 Virogen Drug Discovery, London, United Kingdom3

Received 13 May 2005/ Returned for modification 7 July 2005/ Accepted 1 December 2005

SPD754 (AVX754) is a deoxycytidine analogue nucleotide reverse transcriptase inhibitor (NRTI) in clinical development. These studies characterized the in vitro activity of SPD754 against NRTI-resistant human immunodeficiency virus type 1 (HIV-1) and non-clade B HIV-1 isolates, its activity in combination with other antiretrovirals, and its potential myelotoxicity and mitochondrial toxicity. SPD754 was tested against 50 clinical HIV-1 isolates (5 wild-type isolates and 45 NRTI-resistant isolates) in MT-4 cells using the Antivirogram assay. SPD754 susceptibility was reduced 1.2- to 2.2-fold against isolates resistant to zidovudine (M41L, T215Y/F, plus a median of three additional nucleoside analogue mutations [NAMs]) and/or lamivudine (M184V) and was reduced 1.3- to 2.8-fold against isolates resistant to abacavir (L74V, Y115F, and M184V plus one other NAM) or stavudine (V75T/M, M41L, T215F/Y, and four other NAMs). Insertions at amino acid position 69 and Q151M mutations (with or without M184V) reduced SPD754 susceptibility 5.2-fold and 14- to 16-fold, respectively (these changes gave values comparable to or less than the corresponding values for zidovudine, lamivudine, abacavir, and didanosine). SPD754 showed similar activity against isolates of group M HIV-1 clades, including A/G, B, C, D, A(E), D/F, F, and H. SPD754 showed additive effects in combination with other NRTIs, tenofovir, nevirapine, or saquinavir. SPD754 had no significant effects on cell viability or mitochondrial DNA in HepG2 or MT-4 cells during 28-day exposure at concentrations up to 200 µM. SPD754 showed a low potential for myelotoxicity against human bone marrow. In vitro, SPD754 retained activity against most NRTI-resistant HIV-1 clinical isolates and showed a low propensity to cause myelotoxicity and mitochondrial toxicity.

* Corresponding author. Present address: Boehringer-Ingelheim, Inc., 2100 Rue Cunard, Laval, Quebec H7S 2G5, Canada. Phone: (450) 682-4641. Fax: (450) 682-4642. E-mail: rbethell{at}lav.boehringer-ingelheim.com.

Antimicrobial Agents and Chemotherapy, February 2006, p. 625-631, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.625-631.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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