Fixed conformation nucleoside analogs effectively inhibit excision-proficient HIV-1 reverse transcriptases.

Area of Science:

• Biochemistry
• Virology
• Medicinal Chemistry

Background:

• Nucleoside analogs are key HIV-1 therapies, but resistance emerges via enhanced analog excision.
• Excision of nucleoside analogs by HIV-1 reverse transcriptase (RT) occurs when the analog is at the 3' terminus of the primer strand.

Purpose of the Study:

• To develop novel nucleoside analogs that are resistant to excision by HIV-1 RT.
• To investigate "delayed chain terminators" that inhibit DNA synthesis after incorporating several normal nucleotides.

Main Methods:

• Synthesized nucleoside analogs with fixed pseudosugar conformations (North and South).
• Assessed analog incorporation and DNA chain termination by purified HIV-1 RT.
• Evaluated analog efficacy in cell-based assays against HIV-1 replication.

Main Results:

• North conformation analogs were readily incorporated and allowed limited primer extension before inhibiting DNA synthesis.
• South conformation analogs were poorly incorporated by HIV-1 RT.
• North analogs demonstrated relative resistance to excision by excision-proficient HIV-1 RT mutants.
• These analogs inhibited replication of viruses with excision-proficient RTs.

Conclusions:

• Fixed-conformation nucleoside analogs exhibiting delayed chain termination are resistant to excision by HIV-1 RT.
• These compounds show potential for inhibiting drug-resistant HIV-1 strains.
• Further development of delayed chain terminators may offer complementary HIV-1 treatment strategies.