In search of new inhibitors of HIV-1 replication: synthesis and study of 1-(2'-Deoxy-beta-D-Ribofuranosyl)-1,2,4-triazole-3-carboxamide as a selective viral mutagenic agent

With the emergence of HIV strains resistant or cross-resistant to nearly all antiretroviral regimen, novel therapy approaches have to be considered. As a part of our current work on viral mutagenic compounds, we prepared 1-(2' -deoxy-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2' -deoxy-ribavirin) and its 5' -triphosphate derivative. The nucleoside mutagenic activity was evaluated on HIV-1 NL4-3 in CEMx174 cell culture. After 2.5 months, no reduction on HIV-1 viability was observed. On the other hand, in vitro experiments with purified HIV-1 RT demonstrated that the triphosphate analog can be incorporated opposite to several natural nucleosides.     

Synthesis and biological application of a new heterodinucleotide with both anti-HSV and anti-HIV activity.

A new antiviral drug with both anti-HSV and anti-HIV activity was synthesized by coupling Acyclovir and the acyclic nucleoside phosphonate (R)PMPA. The heterodinucleotide ACVpPMPA encapsulated into autologous erythrocytes was added to human macrophages providing an effective in vitro protection from HSV-1 and HIV-1 replication.     

In Search of New Inhibitors of HIV-1 Replication: Synthesis and Study of 1-(2′-Deoxy-β-D-Ribofuranosyl)-1,2,4-Triazole-3-Carboxamide as a Selective Viral Mutagenic Agent

With the emergence of HIV strains resistant or cross-resistant to nearly all antiretroviral regimen, novel therapy approaches have to be considered. As a part of our current work on viral mutagenic compounds, we prepared 1-(2′ -deoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′ -deoxy-ribavirin) and its 5′ -triphosphate derivative. The nucleoside mutagenic activity was evaluated on HIV-1 NL4-3 in CEMx174 cell culture. After 2.5 months, no reduction on HIV-1 viability was observed. On the other hand, in vitro experiments with purified HIV-1 RT demonstrated that the triphosphate analog can be incorporated opposite to several natural nucleosides.     

Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants

Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.