9-[(2-Hydroxyethoxy)methyl]guanine (acyclovir, 1a) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, ganciclovir, 1b) were transformed to their respective tricyclic derivatives, 3-substituted 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purines 2b, 3a, and 3b. The 6-methyl-substituted compound 2b was obtained following reaction of 1b with bromoacetone. A two-step approach via 1-(2,2-diethoxyethyl) intermediates 4a,b was the most effective for the preparation of the derivatives unsubstituted in the appended ring (3a,b). The novel acyclonucleosides, in particular ganciclovir derivative 2b, proved markedly active against herpes simplex virus type 1 and 2, varicella-zoster virus, and cytomegalovirus.
The regulation of transcription of the human immunodeficiency virus (HIV) is a complex event that requires the cooperative action of both viral and cellular components. In latently infected resting CD4(+) T cells HIV-1 transcription seems to be repressed by deacetylation events mediated by histone deacetylases (HDACs). Upon reactivation of HIV-1 from latency, HDACs are displaced in response to the recruitment of histone acetyltransferases (HATs) by NF-kappaB or the viral transcriptional activator Tat and result in multiple acetylation events. Following chromatin remodeling of the viral promoter region, transcription is initiated and leads to the formation of the TAR element. The complex of Tat with p-TEFb then binds the loop structures of TAR RNA thereby positioning CDK9 to phosphorylate the cellular RNA polymerase II. The Tat-TAR-dependent phosphorylation of RNA polymerase II plays an important role in transcriptional elongation as well as in other post-transcriptional events. As such, targeting of Tat protein (and/or cellular cofactors) provide an interesting perspective for therapeutic intervention in the HIV replicative cycle and may afford lifetime control of the HIV infection.
Hydrogel formulations containing the 1-monoglyceride of capric acid (monocaprin) possess potent in vitro microbicidal activity against HIV and HSV, Chlamydia trachomatis and Neisseria gonorrhoeae. These formulations were studied to determine whether they prevent intracutaneous and intravaginal infections of mice with HSV-2, a virus that is in vitro as sensitive to the virucidal action of the compound as is HIV. In mice intravaginal infection with HSV-2 and the associated mortality was prevented completely when the infection was carried out in the presence of a 20 mM monocaprin containing gel formulation. Similarly, virtually complete protection of lesion development and associated mortality was observed when mice were infected intracutaneously with HSV-2 in the presence of gels containing 10 or 20 mM monocaprin. No irritation or toxicity was observed following application of the gel to the skin or the vaginal mucosa. Hydrogel formulations of monocaprin could thus be pursued as vaginal microbicides for the prevention of sexual transmission of HSV, HIV and other infectious pathogens.
Various new classes of compounds have been recently identified as potent and selective inhibitors of acute HIV infection in vitro. As a rule, these compounds inhibit HIV replication at a concentration of 0.1-1 micrograms/ml, while not being toxic to the host cells at concentrations up to 500 micrograms/ml or higher. Some of the compounds even inhibit HIV replication at a concentration of a few nanograms per ml, thus achieving selectivity indexes up to 100,000, which makes them particularly promising drug candidates for the chemotherapy and -prophylaxis of HIV infections in vitro. These new candidate drugs for the treatment of AIDS fall into the following categories: (i) polyanions (polysulfates, polysulfonates, polycarboxylates and polyoxometalates), which interfere with virus attachment to the cell membrane; (ii) some plant lectins and modified (i.e. succinylated) albumins, which may directly interact with the fusion of the viral envelope with the cell membrane; (iii) bicyclam derivatives, which seem to be targeted at the uncoating (disassembly of the viral proteins from the viral RNA genome); and (iv) reverse transcriptase (RT) inhibitors which fall into two subcategories. The phosphonylmethoxyalkyl derivatives PMEA and FPMPA interact, as chain terminators, with the RT substrate binding site, as do azidothymidine (AZT) and the other dideoxynucleoside analogues. The TIBO derivatives and their congeners interact with a non-substrate binding site at the HIV-1 RT, and thus behave as allosteric inhibitors of the enzyme. The TIBO congeners have proved to be highly specific inhibitors of HIV-1 replication.
No abstract is provided for this article.
This paper presents the design and fabrication procedure of a single-element omnidirectional piezoelectric ultrasound transducer, which can be utilized for under water communication. The transducer consists of a spherical silicon infiltrated silicon carbide (Si-SiC) body and is able to perform communication at 160 kHz with a Q factor of about 5.6 over a distance of more than one meter. The circumferential pressure amplitude of the beam pattern of the transducer varies less than 10 dB, which allows reliable communication between different transducers at an arbitrary orientation with respect to each other.
