Search

Abstract: We have previously reported the potent in vitro HIV-1 anti-reverse transcriptase activity of a 35-mer of 4-thio-deoxyuridylate [(s4dU)35]. In efforts to define its activity in a more physiological system, studies were carried out to determine the stage of viral infection that this compound mediates its anti-viral effect. Results of the studies reported herein show that (s4dU)35 is nontoxic and is capable of inhibiting both single and multi-drug resistant HIV strains (IC50: 0.8–25.4 μg/ml) in vitro. Besides its previously reported anti-RT activity, (s4dU)35 mediated its antiviral action by preventing virus attachment (IC50: 0.002–0.003 μg/ml), and was stable in vitro and slowly degraded by DNAses. Competition studies and fluorescence resonance energy transfer (FRET) experiments indicated that (s4dU)35 preferentially binds to CD4 receptors, but not to CD48. Confocal laser scanning microscopy (CLSM) studies showed that (s4dU)35 did not penetrate into the cells and colocalized with cell surface thioredoxin. Our studies identify (s4dU)35 as a potential novel HIV entry inhibitor that may have utility as either a systemic antiretroviral or as a preventing agent for HIV transmission. [Copyright &y& Elsevier]

The HIV-1 nucleocapsid protein NCp7, which contains two highly conserved zinc fingers, is being used as a novel target for AIDS therapy due to its pivotal role in viral replication and its mutationally intolerant nature. Herein we report a new class of NCp7 inhibitors that possess good antiviral activity with low cellular toxicity. [Copyright &y& Elsevier]

Natural serine protease inhibitors (serpins) elicit sensing of a microbial cell intruder and activate an intrinsic cellular immune response in HIV and HCV infected cells. Here, we demonstrate in vitro inhibition of HSV with serpin antithrombin III (ATIII) early during infection pointing towards inhibition of an entry event. We also found reduction of mortality from 90% to 40% in an abrasion mice model demonstrating a strong reduction of infection in vivo . Our data also indicated that this treatment might be suitable for drug-resistant viruses since high inhibition of an acyclovir-resistant HSV-1 strain was found. Thus, an ATIII tropical treatment might be used for immunocompromised patients where prolonged treatment leads to drug resistant HSV-1 strains. Understanding how ATIII regulates HSV-1 infections may reveal new avenues for therapeutic interventions.