In order to control the rapid spread of HIV it is clear that multiple approaches need to be investigated. One strategy that has shown the potential to reduce transmission in non-human primates is the application of topical microbicides. In addition since it has been demonstrated that other sexually transmitted infections can also increase the transmission of HIV, microbicides that can effectively decrease the spread of other STIs may also be a strategy to decrease HIV transmission. Combinations of approaches that target different stages of the HIV and STIs developmental cycle are desirable not only from the standpoint of reducing resistance but also to attain an additive or synergistic effect. In this proposal we plan on evaluating the ability of small inhibitor molecules with a hydrazone structure to limit the infection of HIV and Chlamydia. Recently we have demonstrated that this class of compounds is able to effectively restrict the growth of Chlamydia in vitro. Furthermore the mechanism of inhibition appears to be linked to the reversible depletion of host iron stores. There is evidence that HIV development can also be modulated by host iron supplies. Therefore, development of microbicides with a common mode of action effective at limiting the growth of both HIV and Chlamydia has the potential to be a powerful weapon in the reduction of this epidemic. We initially plan to test these inhibitors using in vitro system to identify those compounds we will characterize further as to, optimum dose, cytotoxicity, stage of development affected and activity in a genital environment. Compounds that we identify that are active yet have limited cytotoxicity will be formulated as a vaginal microbicide to be tested both in a HIV hu-SCID mouse and Chlamydia mouse genital infection model. Achievement of the aims in this proposal has the potential to uncover an important weapon in the battle against HIV.
In this proposal we plan to identify compounds that have the ability to inhibit the sexually transmitted pathogens, HIV and Chlamydia. We will then use the compounds identified to develop a vaginal preparation (microbicide) and will test it in a mouse model to determine if it can reduce transmission and infectivity of these pathogens. Development of this type of preventative treatment has important implications in fighting the HIV epidemic.
|Cerny, Katheryn L; Van Fleet, Maranda; Slepenkin, Anatoly et al. (2015) Differential Expression of mRNA Encoding Cytokines and Chemokines in the Reproductive Tract after Infection of Mice with Chlamydia trachomatis. Reprod Syst Sex Disord 4:|
|Pedersen, Christian; Slepenkin, Anatoly; Andersson, Sara B E et al. (2014) Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis. PLoS One 9:e110918|
|Forthal, Donald N; Phan, Tran B; Slepenkin, Anatoly V et al. (2012) In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds. Int J Antimicrob Agents 40:354-60|
|Ur-Rehman, Tofeeq; Slepenkin, Anatoly; Chu, Hencelyn et al. (2012) Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion. J Antibiot (Tokyo) 65:397-404|
|Slepenkin, Anatoly; Chu, Hencelyn; Elofsson, Mikael et al. (2011) Protection of mice from a Chlamydia trachomatis vaginal infection using a Salicylidene acylhydrazide, a potential microbicide. J Infect Dis 204:1313-20|
|Chu, Hencelyn; Slepenkin, Anatoly; Elofsson, Mikael et al. (2010) Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae. Int J Antimicrob Agents 36:145-50|