dcyphr | Inhibition of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor.


The drug BI-RG-587 inhibits HIV-1 reverse transcriptase. It is noncompetitive with respect to dGTP. BI-RG-587 inhibited HIV-1 replication in vitro. BI-RG-587 showed little cytotoxic effects until very high concentrations in culture.


Many drug therapies for HIV-1 target the reverse transcriptase because reverse transcriptase is needed for virus replication. Reverse transcriptase is an enzyme that generates DNA from an RNA template. Many effective inhibitors are nucleoside analogs. They stop the nucleotide chain during replication. The first approved drug for HIV-1 infection was the nucleoside analog azidothymidine (AZT). But, there are many side effects with AZT use because AZT can affect normal replication. Viral replication is also not completely inhibited.


Merluzzi et al. proposes new drug therapy against HIV-1. This drug, BI-RG-587, is not a nucleoside analog. So, this drug does not have the usual side effects.


Researchers conducted an enzyme activity assay to determine the Michaelis-Menten constant. The assay revealed BI-RG-587’s noncompetitive mechanism. Merluzzi et al. also tracked HIV-1 replication. They measured the inhibition of the HIV capsid protein p24 in a T cell culture. To measure cytotoxicity in normal cells, they performed a tetrazolium salt (MTT) metabolic assay. They used in situ hybridization and p24 studies to detect HIV-1 in human samples.

Results / Conclusion

The compound BI-RG-587 is a powerful noncompetitive inhibitor of HIV-1 reverse transcriptase. The inhibitor is not a nucleoside analog structure, so it will not have the same side effects as AZT. BI-RG-587 does not compete with deoxyguanosine triphosphate (dGTP) (Figure 2). The noncompetitive character suggests BI-RG-587 works by allosteric binding to the reverse transcriptase. BI-RG-587 inhibited the reverse transcriptase even with different templates and primers. As the concentration of BI-RG-587 increases, reverse transcriptase inhibition increases. As a result, there is less viral replication. 

BI-RG-587 is very specific for HIV-1 reverse transcriptase. It does not inhibit other viruses, human DNA polymerases, or other enzymes (Table 1). BI-RG-587 causes partial inhibition of HIV-1 ribonuclease (RNase) H activity. The partial inhibition may reflect BI-RG-587 binding to a site other than the active site. But, BI-RG-587 binding causes a greater conformational change of the reverse transcriptase than RNase H. 

Very low amounts of BI-RG-587 can inhibit HIV-1 replication. The IC50 against HIV-1 strain IIIb was 40 nM in T cells. BI-RG-587 causes cytotoxic effects only at extremely high concentrations (>105 nM) (Figure 3). BI-RG-587 inhibited three HIV virus strains equally well: HIV-1IIIb, HIV-1RF, and HIV-1UMGL. BI-RG-587 also inhibited the replication of HIV-1 primary isolates in four patients. These patients were undergoing AZT therapy.