Background Combined antiretroviral therapy has drastically reduced mortality and morbidity of HIV-infected people. virus-based assay was used measuring activation of a reporter gene upon fusion of two distinct cell populations. Flow cytometry was performed in competition assays for the binding of several antibodies targeting different sites of the viral envelope glycoprotein gp120 or the receptor CD4 or the coreceptors CXCR4 and CCR5. Results Four compounds inhibited replication of a prototypic R5 (BaL) and X4 (IIIB) laboratory-adapted HIV-1 strain at low micromolar concentrations in the absence of cytotoxicity. Approximately a ten fold greater activity was achieved against the X4 as compared to the R5 strain. The compounds blocked X4 and R5 HIV-1 fusion a step of viral entry. This activity appeared specific for HIV-1 as entry of human herpesvirus 6 (HHV-6) and Polyphyllin A influenza virus was not substantially affected. Further investigation of the inhibitory mechanism revealed that these new molecules target the viral envelope rather than the coreceptors as previously shown for a congener of the same class characterized by a long plasmatic half-life. Indeed ND-4043 the most active compound specifically competed with binding of monoclonal antibodies against the CD4-binding site (CD4-BS) and coreceptor-binding site (CoR-BS) of gp120. These compounds displayed broad anti-HIV activity because they inhibited different major R5 X4 and significantly dualtropic R5X4 HIV-1 isolates. From the four derivatives tested the dimeric compounds were Polyphyllin A stronger compared to the monomeric ones consistently. Conclusions Particular their particular features these substances represent promising applicants for even more exploitation and advancement seeing that anti-HIV therapeutics. Electronic supplementary materials The online edition of this content (doi:10.1186/s12967-015-0461-9) contains supplementary materials which is open to certified users. Background Regardless of the achievement of global treatment and avoidance strategies HIV infections rates remain growing world-wide and AIDS continues to be a significant open public wellness burden in low- to middle-income countries. Mixture antiretroviral therapy (Artwork) encompassing a cocktail of medications targeting different guidelines of the viral life cycle [1] is the standard treatment regimen resulting in slowed disease progression and significantly prolonged life expectancy of patients. Indeed current inhibitors include a wide array of viral targets such as viral enzymes (reverse-transcriptase protease integrase) viral structural proteins (gp41) and host cellular components such as the chemokine receptor CCR5 which is the major HIV-1 coreceptor in addition to CXCR4. Despite these advancements Polyphyllin A mutations in HIV-1 can arise which confer Polyphyllin A resistance to drugs often resulting in resistance to entire inhibitor classes. Moreover long-term drug toxicity although reduced in comparison to early drugs remains a critical factor Rabbit polyclonal to PHC2. in determining the patient outcome and long-term health. Therefore it is evident that clinical management of HIV requires novel drugs to be continuously available for inclusion in ART regimens. Herein we report the anti-HIV-1 activity of novel synthetic molecules and elucidate their mechanism of action. They belong to the suradista chemical class which shares certain features with the anti-trypanosoma drug suramin [2 3 and the antibiotic distamycin [4]. Suramin itself was shown early on to counteract the cytopathic effect of HIV [5] but in the following clinical trials it did not result as a clear benefit for AIDS patients [6 7 Despite binding to the minor groove of DNA most of the biological effects of distamycin were likely due to the conversation with membrane structures [8]. The anti-angiogenic activity of suradista molecules has been investigated [9] as well as in a clinical phase-I study for the treatment of cancer [10]. Several sulfonated and phosphonated suradista molecules have been evaluated as HIV inhibitors [11] and certain congeners have been shown to interact with HIV coreceptors [12]. We here demonstrate that novel suradista compounds act as HIV entry inhibitors targeting crucial determinants of the viral envelope of both R5 and X4 HIV-1 viruses. This amazing feature along with the pharmacokinetic properties of members of the suradista family warrants further investigation and development of these molecules. Methods Reagents The experimental compounds herein tested were dissolved in DMSO at a stock concentration of 15 mM aliquoted and frozen at -20°C. The aliquot in use was kept at room heat (rt). Control.