Drug Susceptibility Profile of OBP-601, a Novel NRTI, Using a Comprehensive Panel of NRTI- or NNRTI-resistant Viruses
Jan Weber*1, J Weberova1, A Vazquez1, Y Urata2, T Matsuda2, R Shafer3, E Arts4, and M Quinones-Mateu1
1Diagnostic Hybrids Inc, Cleveland, OH, US; 2Oncolys BioPharma, Tokyo, Japan; 3Stanford Univ, Palo Alto, CA, US; and 4Case Western Reserve Univ, Cleveland, OH, US
Background: Despite the relative success of ART, emergence
of drug-resistant HIV-1 variants continues to be the major cause for treatment
failure. OBP-601 (4’-Ed4T) is a novel nucleoside analog with potent anti-HIV-1
activity and limited cellular toxicity, which has a unique in vitro resistance
profile. Here we evaluated the ability of OBP-601 to inhibit the replication of
multi-drug resistant viruses, and its potential use in combination therapy.
Methods: A panel of 40 3’Gag/PR/RT-recombinant
viruses were generated using polymerase chain reaction (PCR) products from
clinical samples harboring selected sets of NRTI resistance mutations (e.g., NAM, TAM41, TAM67, M41l+V118I, K65R, L74V, and Q151M, plus K103N + M184V). These viruses
were employed in drug susceptibility assays to test the activity of OBP-601
alone or in combination with zidovudine (AZT), stavudine (d4T), abacavir (ABC),
tenofovir (TDF), lamivudine (3TC), efavirenz (EFV), nevirapine (NVP), lopinavir
(LPV), atazanavir (ATV), and darunavir (DRV). Viral replication was quantified
using luciferase expression and/or an in-house reverse transcriptase (RT)
assay, and 50% (IC50) inhibition concentration were determined.
Antiviral isobolograms were calculated for the combination studies.
Results: OBP-601 susceptibility of recombinant
viruses carrying wild type 3’Gag/PR/RT sequences ranged from 0.76 to 5.80 µM in
our in vitro system, slightly lower than the parental compound d4T (1.57
to 6.06 µM). The anti-HIV-1 activity of OBP-601 was reduced in most viruses
carrying NAM (5- to 10-fold), TAM41 (0.3- to 4.3-fold), and TAM67 (1.6- to
7.8-fold) resistance mutations, together with K103N + M184V. Interestingly,
viruses carrying the Q151M substitution were hypersusceptible to OBP-601 (0.1-
to 0.2-fold), even in the presence of K65R (0.7- to 1.2-fold). More important,
OBP-601 showed strong (AZT, EFV) to moderate (ABC, TDF, NVP) synergistic
interaction with different antiretroviral drugs in wild type viruses. Similar
results were obtained with 3TC, EFV, and ABC in viruses carrying M184V, K103N,
and Q151M, respectively.
Conclusions: This novel nucleoside analog has proven
to be more potent and less toxic than d4T. Its unique resistance profile, effectiveness
against drug-resistant viruses (e.g., carrying the Q151M complex), and the
synergistic effect with other reverse transcriptase inhibitors (RTI) (in both
wild type and drug-resistant viruses) warrant further investigation for its
potential use in combination therapy against HIV-1.