HIV-1 integrase inhibitors as new components of antiviral therapy

Abstract

We present a brief summary of new technical developments of passive and active vibration controls which we have performed for the last several years partly as an international collaborative R&D project on Smart Materials and Structural Systems sponsored by the Japanese Ministry of Economy, Trade and Industry. In connection with the passive damping control, shape memory alloys (SMAs) were used as damping elements. To examine the effect of damping enhancement, beams with SMA films bonded onto them or SMA wires embedded into them were made, and free damped oscillations were measured. The damping coefficient increased by more than 100% compared with the beams without SMAs. Thermodynamic behaviors of an SMA wire and film were also investigated experimentally and numerically. In active vibration control, a new concept of smart material systems was proposed. That is a partially magnetized alloy, which is stiff and strong enough as a structural element and responds sufficiently quickly as an actuator due to an electromagnetic force. A simplified experiment and numerical simulation were performed and the results showed the feasibility of the proposed smart material system using the electromagnetic force.

Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting

“…The binding of the DNA substrate by IN occurs both in its catalytic and C-terminal domains 39, 40 . Since we introduced point mutations in the helix α6 that links these domains, any misfolding in the helix should cause a loss of the IN catalytic activity.…”

“…To rule out that the loss of binding activity by the IN mutants could result from their misfolding, we tested the catalytic activity of three IN point mutants in 3′-processing and strand transfer reactions. The binding of the DNA substrate by IN occurs both in its catalytic and C-terminal domains 39 , 40 . Since we introduced point mutations in the helix α6 that links these domains, any misfolding in the helix should cause a loss of the IN catalytic activity.…”

NHEJ pathway is involved in post-integrational DNA repair due to Ku70 binding to HIV-1 integrase

“…It is performed by viral enzyme integrase (IN) that being in a multimeric form [1–3], binds viral DNA and catalyzes the cleavage of dinucleotides from both its 3′-ends. The 3′-processed viral DNA in complex with IN and a number of viral and cellular proteins is then transported into nucleus, where IN catalyzes the second step of integration by inserting each of the processed viral DNA 3′-ends into one strand of cellular DNA [4, 5]. This insertion results in the formation of 5 nucleotide gaps [5–7].…”

Clinical Use of Inhibitors of HIV-1 Integration: Problems and Prospects

“…Moreover, IN does not have a cell equivalent; therefore, the inhibitors that specifically suppress its catalytic activity are supposed to have no effect on the cell processes and should be less toxic for the cell and the entire organism in comparison to the inhibitors of other stages of the HIV replication cycle. Over many years, the development of integration inhibitors has been pursued, with various drugs capable of blocking IN described in minute detail in numerous reviews [13– 19 ]. The present review is devoted to state-of-the-art studies in the field of application of raltegravir and its analogues as HAART components.…”