In this work we have developed specific inhibitors of HIV-1 reverse transcriptase by targeting the RNA/DNA duplex that is a principal substrate of the enzyme. To accomplish this, we have developed what we are calling the "weak intercalator" approach, wherein we attempt to simultaneously bind multiple weak intercalators to critical polymerase nucleic acids. We define weak intercalators as planar sp<sup>2</sup> hybridized molecules with only two cycles, that have poor binding affinity individually and can only bind with high affinity if two or more weak intercalation events can take place. Using this approach, we have identified linear and cyclic molecules that present two weak intercalators that can inhibit HIV-1-RT 50 to 100 times more effectively than single weak intercalators. Specifically, a cyclic peptide motif that presents two quinoxaline rings inhibits HIV-1-RT at low µM concentration, shows no inhibition of DNA polymerase and in addition maintains a majority of its inhibitory power in the presence of 90,000 fold excess duplex DNA. These results suggest that the weak intercalator approach may prove effective as a way of targeting increasingly complex nucleic acid structures in a highly specific manner.