INHIBITION MECHANISMS OF HIV-1, MO-MULV AND AMV REVERSE TRANSCRIPTASES BY KELLETININ-A FROM BUCCINULUM-CORNEUM

Kelletinin A [ribityl pentakis (p-hydroxybenzoate)] (KA), an inhibitor of HTLV-1 replication isolated from Buccinuhum corneum, showed a nonc ompetitive inhibitory activity with respect to the template primer and to dTTP in the poly(rA) . oligo(dT)(12-18)-directed reaction of HIV-1 , Mo-MuLV and AMV reverse transcriptases (RT). Analysis of natural and synthetic KA-related compounds showed that the inhibitory activity wa s strictly related to the structural peculiarities of the molecule. In the presence of DNA as template primer the inhibition mechanism was d rastically modified: HIV-1 RT activity was stimulated by low concentra tions of KA and was inhibited by increasing the concentration of the c ompound, while Mo-MuLV and AMV activities were irreversibly inhibited by the formation of a non-reactive complex. The RNase H activities of these RTs were not affected by KA. The results of this study suggest a different mechanism of interaction of Kelletinins with HIV-I RT compa red with other non-nucleoside inhibitors. A possible use of these drug s in combination therapy and in the design of structure-based reverse transcriptase inhibitors is discussed.