Modifications in the branched arms of a class of dual inhibitors of HIV and EV71 replication expand their antiviral spectrum

We have previously reported a new class of dendrimers with tryptophan (Trp) residues on the surface that show dual antiviral activities against HIV and enterovirus EV71. The prototype compound of this family is a derivative of pentaerythritol with 12 peripheral Trp groups and trivalent spacer arms. Here a novel series of dendrimers with divalent and tetravalent branched arms, instead of the trivalent ones present on the prototype, has been synthesized and its activity against HIV, EV71 and a panel of 16 different viruses and other pathogens has been determined. Convergent or divergent approaches have been used for the synthesis of these compounds. Our findings demonstrate that only compounds with tetravalent branched arms showed the same anti-HIV and anti-EV71 activity of the prototype (low micromolar) and even gain significant antiviral activity against new pathogens such as HSV-2, adenovirus-2, human corona virus and respiratory syncytial virus, being the first members of the Trp dendrimer family that showed activity against those viruses. As the prototype, these compounds also showed low-nanomolar activity against a representative EV71 clinical isolate. Experimental work carried on to determine the mode of action of the most potent IIa, containing tetravalent branched arms, demonstrated that it interacts with the viral envelopes of HIV, EV71 and HSV-2 and thus may prevent virus attachment to the host cell. These results support the interest of this new series of Trp dendrimers and qualify them as useful prototypes for the development of novel inhibitors of viral entry with broad antiviral spectrum.