Natural Product Kuwanon‐L Inhibits HIV‐1 Replication through Multiple Target Binding

Abstract

In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Thus, new compounds with original modes of action are continuously required, and natural products have ever been a very interesting class of pharmacologically active molecules. Some of them have been used since ancient times against viral infections. Here we present a work in which we suggest that kuwanon-L, a natural product active as an HIV-1 integrase (IN) inhibitor, might exert its overall antiviral activity through binding to multiple viral targets. Specific enzymatic tests, together with a time-of-addition (TOA) experiment, support our hypothesis of binding both to IN and to reverse transcriptase (RT). Overall, this compound can be considered an attractive lead for the development of new classes of antiviral agents able to overcome the problem of resistance, due to its ability to exert its action by binding simultaneously to multiple viral targets.

Prenylated phloroglucinols from Hypericum scruglii, an endemic species of Sardinia (Italy), as new dual HIV-1 inhibitors effective on HIV-1 replication

“…Since HIV-1 RNase H and IN domains have striking similarities, in order to evaluate if the compounds able to inhibit HIV-1 RNase H function could act through a multitarget profile, we investigated them also on IN catalytic activities. It is well known, in fact, that compounds capable to inhibit the HIV-1 RNase H activity may also affect the HIV-1 IN activity [ 15 , 17 , 39 , 45 , 46 , 80 ]. Hence, we evaluated their ability to inhibit the HIV-1 IN strand transfer reaction in the presence of the LEDGF/p75 cellular cofactor, using Raltegravir as positive control ( Table 2 ).…”

“…Significant research and development over the last 25 years into antiviral drug discovery has resulted in the identification of important antiviral drugs [ 7 ]. In particular, a number of attempts have been made in the fight against HIV-1 infection and several natural compounds able to inhibit the viral enzymes have been reported [ 9 – 17 ]. However, so far all anti HIV-1 approved drugs were obtained only by chemical synthesis.…”

“…For many years, the drug discovery was based on searching for new compounds or new targets, recently the development of single molecules targeting both viral HIV-1 RT-associated RNase H and RNA-dependent DNA polymerase (RDDP) functions, or RNase H and IN functions (dual inhibitors) has been proposed as an interesting approach [ 17 , 26 , 45 – 49 ]. This innovative strategy could offer the possibility to reduce the toxicity associated to the co-administration of several classes of drugs [ 18 , 40 ].…”

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

“…Twenty thousand TZM-bl cells/well were seeded in 96-well plates in complete DMEM supplemented with 30 μg/mL DEAE-dextran (Sigma-Aldrich). Three hundred times the 50% tissue culture infective dose (TCID50)/mL of each strain was pretreated for 1 h at 37°C with six serial dilutions (20000 nM to 3.2 nM) of each compound and then added to the cells, as previously described [ 29 – 32 ]. Vehicle (0.1% dimethyl sulfoxide [DMSO])-treated cells served as a negative control.…”

From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors

“…RNA-dependent DNA polymerase (RDDP) activity was measured as described 17 using and different amounts of enzymes according to a linear range of dose-response curve: 6 ng wt RT; 19 ng V108F RT; 45 ng Y188A RT; 30 ng W229A RT; A502F RT. The Yonetani-Theorell analysis was performed as previously described 41 , 42 .…”