Research Article: Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides

Date Published: June 5, 2018

Publisher: Public Library of Science

Author(s): Cristina Tintori, Giulia Iovenitti, Elisa Rita Ceresola, Roberto Ferrarese, Claudio Zamperini, Annalaura Brai, Giulio Poli, Elena Dreassi, Valeria Cagno, David Lembo, Filippo Canducci, Maurizio Botta, Giovanni Maga.


Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches. For this reason, combinations of different compounds with mixed antiviral and antiretroviral activity are thoroughly investigated Here we report the synthesis and the biological evaluation of a novel series of rhodanine derivatives, which showed to inhibit both HIV-1 and HSV-1/2 replication at nanomolar concentration, and were found to be active also on acyclovir resistant HSV-2 strains. The compounds showed a considerable reduction of activity in presence of serum due to a high binding to serum albumin, as determined through in vitro ADME evaluations. However, the most promising compound of the series maintained a considerable activity in gel formulation, with an EC50 comparable to that obtained for the reference drug tenofovir. Moreover, the series of compounds showed pharmacokinetic properties suitable for topical formulation, thus suggesting that the novel rhodanine derivatives could represent effective agents to be used as dual anti HIV/HSV microbicides in PrEP approaches.

Partial Text

Implementation of extensive patients’ treatment and prevention strategies in the global response against human immunodeficiency virus type 1 (HIV-1) epidemic has resulted in significant reduction of new infections worldwide. Nevertheless, sexually transmitted infections (STIs), including HIV-1, represent a major global burden, particularly in resource limited regions [1]. Moreover, since 2010, no significant reduction of novel HIV-1 infections was recoded in most countries, suggesting that current efforts, including the increase access to antiretroviral treatment are not sufficient to end the AIDS epidemic.

Several studies confirmed the efficacy of topical PrEP approaches to limit the burden of novel HIV-1 infections and to enhance global efforts to eradicate this virus. However, several co-factors may limit the efficacy of PrEP approaches. Patients’ compliance due to the need of frequent or fastidious topical applications was initially shown as a critical cause of protection failure [9,10]. Therefore, the usage of long-acting formulations or slow releasing devices significantly ameliorated patients’ compliance and PrEP efficacy. Unfortunately, independently from the type of vehicle and release kinetic of current PrEP formulations, the presence of circulating strains already resistant to available antiretroviral agents (present in the PrEP preparations) or the co-presence of other genital infections such as those due to HSV-1 or 2, which increase patient’s susceptibility to HIV-1 infection, remain unsolved problems [11]. During HSV-1 or 2 infections, the mucosal barrier damage and the increased number of inflammatory cells susceptible to HIV-1 infection facilitate HIV-1 transmission. Interestingly, despite the very limited anti HSV-2 activity of tenofovir [16], in the CAPRISA 004 study, TFV PrEP reduced occurrence of HSV-2 infection by 50%, possibly enhancing the overall observed efficacy against HIV-1. Thus, multipurpose combinations of different compounds with antiviral and antiretroviral activity are intensively investigated, sometimes also associated with unintended pregnancy prevention compounds [23–28]. Compounds acting on both viruses such as the rhodanine derivatives described in this paper, represent effective agents to be used in candidate PrEP approaches without the need of dual-agents preparations. We demonstrated in our previous paper that these molecules block very early step in virus replication, preventing viral entry into cells. The inactivity against HPV-16, a not enveloped virus implicated in sexually transmitted infections suggests that the viral envelope could be implicated in the mode of action of our compounds. Preliminary data in our possess corroborate our hypothesis demonstrating that our compounds act on specific components of the viral envelope. These results will be reported in a subsequent more specific manuscript. Compounds targeting efficiently the entry of both HIV-1 or HSV-1 and 2 may represent a very attractive strategy to prevent target cell infection, with limited cell toxicity and reduced need of tissue penetration.




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