Optimization of a Class of Tryptophan Dendrimers That Inhibit HIV Replication Leads to a Selective, Specific, and Low-Nanomolar Inhibitor of Clinical Isolates of Enterovirus A71

Abstract

Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range. Enterovirus A71 (EV71) is a small virus (ϳ30 nm) with a singlestranded positive-sense RNA genome of ϳ7.4 kb that belongs to the genus Enterovirus of the family Picornaviridae (1, 2). EV71 is the etiologic agent of hand, foot, and mouth disease (HFMD), a mild syndrome that most frequently affects children younger than 6 years and that is characterized by the development of fever with skin vesicles on the palms and feet, as well as ulcers on the oral mucosa (3). Unlike other HFMD-associated enteroviruses, EV71 can also cause severe neurological problems, such as aseptic meningitis and brain stem encephalitis, which can lead to cardiopulmonary failure and death (4-6). After having suffered from such neurological complications, survivors often have permanent neurological sequelae, such as delayed neurodevelopment, reduced cognitive function, and polio-like paralysis (7). Similar to other human enteroviruses, such as poliovirus, transmission of EV71 occurs through the fecal-oral route (8).In recent years, large outbreaks of EV71 have been reported throughout the world, and they have been particularly severe in the Pacific region of Asia, with a high number of fatal cases among children (9-11). So far, there is no drug on the market to treat or prevent this infection. An inactivated EV71 vaccine was recently approved in China (12), but it may induce only limited crossneutralization between EV71 genogroups, which does not make it suitable for widespread use.Recently, we reported on the anti-HIV activity of a dendrimer family containing different central scaffolds and multiple (9 to 18) peripheral tryptophan (Trp) groups (Fig. 1, compounds 1 to 11) that are linked to the dendrimer branches through an amino group. These compounds were shown to inhibit an early step in the replication cycle of HIV by interacting with glycoproteins gp120 and gp41 of the HIV envelope (13). Further exploration in virus-cell-based assays for broad-spectrum antiviral activity against other viruses (herpes simplex viruses 1 and 2, vaccinia virus, varicella-zoster virus, vesicular stomatitis virus, respiratory syncytial virus, reovirus 1, Sindbis virus, Punta Toro virus, cytomegalovirus, influenza virus A [subtypes H1N1 and H3N2], influenza virus B, feline coronavirus, and feline herpes virus) did not reveal any inhibitory activity, except when evaluated against EV71, a virus whose structure and mechanism of replication are completely different than those of HIV. This unexpected and intriguing observation prompted us to inv...

Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid

“…From the series of Trp dendrimers endowed with high in vitro potency against EV-A71 replication, MADAL385 ( Fig 1A ) was selected for further mechanistic studies (EC 50 against the lab-adapted BrCr strain: 0.29 ± 0.07 μM, CC 50 : 30.0 ± 2.5 μM) [38]. In a cytopathic effect (CPE)-based reduction assay, MADAL385 is ~1,800 to ~20,000-fold more effective against a representative EV-A71 clinical isolate (EV-A71_11316, geno-group B2) than two earlier reported EV-A71 inhibitors, namely pirodavir [31] and suramin [39] ( S1 Fig ).…”

“…Our earlier biological studies demonstrated that MADAL derivatives inhibit HIV entry into its target cell by interaction with glycoproteins gp120 and gp41 of the viral surface [36]. For EV-A71, we demonstrated that MADAL derivatives exhibit low micromolar activity against the lab-adapted strain BrCr and low-nanomolar/high-picomolar activity against a large panel of EV-A71 clinical isolates from different genogroups and various geographic origins [38]. Structure-activity relationship (SAR) studies on the periphery and central scaffold of MADAL highlighted the importance of free carboxylic groups for optimal antiviral activity, those carried by Trp or Tyr residues.…”

“…Recently, we discovered a class of inhibitors with dual activity against HIV and EV-A71 [36,37]. The lead compound of this family, MADAL385, is a tetrapodal derivative with a pentaerythritol core, 4 trivalent spacer arms and 12 tryptophan (Trp) residues on the periphery [38]. Because the tryptophan dendrimers are linked to the central scaffold through their amino groups, their carboxylates are free and exposed to the solvent.…”

Dendrimers and Dendritic Materials: From Laboratory to Medical Practice in Infectious Diseases

“…Currently, neither vaccines nor therapies have been approved to prevent or treat EV71 infection, representing an important global problem but specially in the Asian southeast [ 85 ]. A tryptophan-decorated pentaerythritol dendrimer was especially active towards EV71 in some clinical isolates in the low nM–high pM range [ 86 ]. As EV71 is mainly transmitted through fecal–oral route, these dendrimers could be used as a prophylactic method after their oral administration, thus avoiding the transfer of EV71 from the gut to the bloodstream.…”

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

“…Dendrimer 1 inhibits not only the laboratory strains of EV71 (BrCr strain) but also a large panel of clinical isolates (belonging to each of the genogroups) in the low-nanomolar/high-picomolar range (Rivero-Buceta, 2016). Recently, it was demonstrated that 1 targets residues of the structural protein VP1, particularly the region that forms the 5-fold vertex of the viral capsid, in turn blocking the binding of the virus to the host cell (Sun, 2019).…”