3rd International Workshop on HIV Drug Resistance & Treatment Strategies


23-26 June 1999, San Diego, California, USA

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COMBINATION ANTI-HIV AND RESISTANCE PROFILES FOR SJ-3366: A NEW NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR OF HIV-1 WITH ACTIVITY AGAINST HIV-2

Antiviral Therapy 1999;4 (Suppl 1):4 (abstract no. 4)

RW Buckheit Jr1, TL Stup1, V Fliakas-Boltz1, JM Russell1, J-W Lee2, S-H Lee2, J-W Oh2, H-S Kwon2, S-G Chung2 and E-H Cho2
1Southern Research Institute, Frederick, Maryland USA; and 2Samjin Pharmaceutical, Seoul, Korea

We have identified and characterized a potent new non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1 that also is inhibitory against HIV-2. SJ-3366 inhibits HIV-1 replication at concentrations below 1 nM with a therapeutic index of greater than 4,000,000. SJ-3366 inhibited HIV-2 at a concentration of approximately 150 nM with a therapeutic index of nearly 20,000. Mechanistic evaluations indicate that SJ-3366 inhibits HIV-1 by two means: inhibition of RT and inhibition of virus attachment. The anti-attachment mechanism is also operative against HIV-2. Biochemically, SJ-3366 exhibited a Ki value of approximately 2.7-3.8 nM in replicate assays with a mixed mechanism of inhibition (both the Km and Vmax were affected by the compound). In these enzymatic assays, SJ-3366 was specific for HIV-1 and did not inhibit HIV-2 RT. Typical of most NNRTIs, the compound lost activity when challenged with HIV-1 strains possessing Y181C, K103N and Y188C amino acid changes in the RT. Combination anti-HIV assays indicated an additive interaction with all tested compounds with the exception of didanosine, where a synergistic interaction was observed. No antagonism or synergistic toxicity was observed. We have selected for a resistant strain that is completely insensitive to SJ-3366. This resistant strain has been characterized for mutations conferring resistance to both virus attachment and RT inhibition. Other resistance engendering mutations may confer increased fitness or compensate for fitness-decreasing amino acid changes. Based on its significantly elevated therapeutic index and multiple mechanisms of anti-HIV action, SJ-3366 represents an exciting new compound for use in HIV-infected individuals.

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