Human immunodeficiency virus (HIV)Gag protein targets to the plasma membrane and assembles into viral particles. In the next round of infection, the mature Gag capsids disassemble during viral entry. Thus, Gag plays a central role in the HIV life cycle. Using a yeast membrane-associated two-hybrid assay based on the SOS-RAS signaling system, we developed a system to measure the Gag-Gag interaction and isolated 6 candidates for Gag assembly inhibitors from a chemical library composed of 20,000 small molecules. When tested in the human MT-4 cell line and primary peripheral blood mononuclear cells, one of the candidates, 2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine (BMMP), displayed an inhibitory effect on HIV replication, although a considerably high dose was required. Unexpectedly, neither particle production nor maturation was inhibited by BMMP. Confocal microscopy confirmed that BMMP did not block Gag plasma membrane targeting. Single-round infection assays with envelope-pseudotyped and luciferase-expressing viruses revealed that BMMP inhibited HIV replication postentry but not simian immunodeficiency virus (SIV) or murine leukemia virus infection. Studies with HIV/SIV Gag chimeras indicated that the Gag capsid (CA) domain was responsible for the BMMP-mediated HIV postentry block. In vitro studies indicated that BMMP accelerated disassembly of HIV cores and, conversely, inhibited assembly of purified CA protein in a dosedependent manner. Collectively, our data suggest that BMMP primarily targets the HIV CA domain and disrupts viral infection postentry, possibly through inducing premature disassembly of HIV cores. We suggest that BMMP is a potential lead compound to develop antiretroviral drugs bearing novel mechanisms of action.Over 2 decades, research has developed antiretroviral therapy (ART) with a combination of antiretroviral drugs for human immunodeficiency virus type 1 (HIV-1) infection (10). ART has dramatically improved the survival of HIV-1-infected individuals. Current ART involves a combination of inhibitors of HIV-specific enzymes, such as protease (PR), reverse transcriptase (RT), and integrase (IN). In some cases, inhibitors of HIV-1 entry are also used. However, the emergence of HIV-1 variants resistant to antiretroviral drugs during ART stresses the need for novel HIV-1 inhibitors against distinct targets.Multiple screening approaches have been employed for HIV-1 drug discovery (37) and have successfully discovered HIV-1 inhibitors that are currently available: nucleoside analogue RT inhibitors were discovered by HIV replication assays (23) and PR inhibitors were produced by structure-based drug design (25). In general, cell-free assays allow discovery of compounds with a relatively low 50% effective dose (ED 50 ) in vitro. However, many such compounds often fail to inhibit HIV-1 replication in in vivo assays, because they may not penetrate the cell membrane or may easily be catalyzed in metabolic environments. Also, possible toxic effects of the compounds must be tested in a subsequent c...

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Dislocation motion at low temperatures in high purity Nb is studied by using dislocation breakaway phenomena. A strain amplitude dependence at constant temperatures or a temperature dependence at constant strain amplitude of the internal friction and the resonant period of vibration of about 600 Hz is measured to detect dislocation breakaway. Three stages of dislocation breakaway probably from hydrogen pinners can be detected below liquid nitrogen temperature. Activation parameters obtained from the breakaway measurements suggest that they correspond with the three types of dislocation motion: the kink diffusion along non‐screw dislocations takes place at the lowest temperatures which is followed by the kink diffusion along screw dislocations, then the kink pair formation on non‐screw dislocations takes place. After these breakaways, two relaxation peaks (the α1‐ and α2‐peaks) emerge in the internal friction which are considered to be caused by the last two types of dislocation motion.

Dedicated to Prof. Dr. A. SEECER on the occasion of his 60th birthday Dislocation motion a t low temperatures in pure and hydrogen free Nb is investigated after defor, mations a t 77 K, RT, or 420 K by an internal friction technique a t about 600 Hz. The a-peak in hydrogen free (Pd coated) Nb specimens after deformation at 77 H and warm u p t o RT is observed as a very broad peak a t around 60 I ( . Ageing a t 420 K causes the preferential suppression of thc higher temperature part of the a-peak and reveals the a,-peak a t around 40 K. This suppression is probably associated with dislocation pinning by C, N, or 0 impurities. The subtraction of t,his a,peak from the virgin a-peak gives the a,-peak a t around 60 K. On the other hand, deformation at R T (or 420 K) always causes an absorption of hydrogen into the specimen and gives rise to the small a,-peak and the large hydrogen cold work (HCW) peak. During ageing at 420 K (hydrogen degassing treatment) of this specimen, the HCW peak is suppressed starting from the higher temperature side and finally disappeared and the a,-peak grows up a t about 40 K. These results and also the activation volume of 5b3 or less determined for the a,-peak and about 30b3 for the a,-peak suggest that the a,and the a,-peaks are associated with the kink diffusion process in screw dislocations and the kink pair formation process on non-screw dislocations, respectively. The activation parameters determined for these peaks are E w 70 meV and 70 w 1.0 >: s for the a,-peak and E m 75 meV and zo m 3 x Bei tiefen Tempcraturen wird in reinem und wasserstofffreiem Nb die Versetzungsbewegung nach Deformation bei 77 K, R T oder 420 K mittels Messung der inneren Reibung bei 600 Hz untersucht. Das a-Maximum in wasserstofffreien (Pd-bedeckten) Nb-Proben nach Deformation bei 77 K und Erwarmung auf RT wird als sehr breites Maximum bci etwa 60 K beobachtet. Temperung bei 430 H verursacht die bevorzugte Unterdriickung des hoheren Temperitturanteils des a-Maximums und ergibt ein a,-Maximum bei etwa 40 K. Diese Unterdruckung ist wahrscheinlicli verkniipft mit einer Versetzungsverankerung durch C-, Noder 0-Storstellen. Die Substraktion dieses a,-Maximums vom jungfraulichen a-Maximum ergibt das a,-Maximum bei etwa 60 K. Andererseits verursacht eine Deformation bei RT (oder 420 K) eine Absorption von Wasserstoff in der Probe und gibt AnlaB zu dem kleinen, a,-Maximum und dem grol3en Cold Work Wasserstoff (HCW)-Maximum. Wahrend der Temperung bei 420 K (Wasserstoffentgasungsbehandlung) dieser Probe wird das HCW-Maximum unterdruckt, beginnend auf der Hochtemperaturseite, und verschwindet schlieolich, wahrend das a,-Maximum erneut bei etwa 40 K wachst. Diese Ergebnisse sowie das Aktivierungsvolumen von 5b3 oder kleiner, ftir das a,-Maximum und etwa 30b3 fur das a,-Rlaximum weisen darauf hin, da13 die a,-und a,-Maxima verknupft sind mit einem Kinkdiffusions-prozeB der Schraubenversetzungen bzw. einem KinkpaarbildungsprozeB der Nicht-Schraubenversetzungen. Die fur diese Maxima bestimmten Aktivierungsparameter sind E ...