Case Report

Guillain-Barré syndrome associated with Zika virus infection

Guillain–Barre syndrome (GBS) is an autoimmune neurological disease considered as the most common cause of acute flaccid paralysis worldwide. In terms of etiology and pathogenesis, upper respiratory infection, gastroenteritis, and Zika virus are among the well-documented infections preceding the appearance of GBS. To what extent SARS-CoV-2 is involved in GBS is still controversial as will be explained later in this chapter. The first manifestations of GBS usually include progressive weakness of limbs accompanied by the absence of or reduced reflexes. Another presentation could be facial diplegia with paraesthesia or a pharyngeal–cervical–brachial manifestation. GBS is divided into various subtypes: acute axonal motor neuropathy (AMAN) and acute inflammatory demyelinating neuropathy (AIDP). Miller-Fisher syndrome and Bickerstaff brainstem encephalitis are subtypes that are clinically different from GBS but serologically similar to it. Miller-Fisher syndrome, characterized by ataxia, areflexia, and ophthalmoplegia, is considered to be a subtype of GBS, firstly because CSF examination of patients with Miller-Fisher syndrome revealed an albumin-cytologic dissociation and secondly some of the patients might develop GBS later in the clinical course of the disease.

Direct targeting of essential viral enzymes such as proteases, polymerases, and helicases has long been the major focus of antiviral drug design. Although successful for some viral enzymes, targeting viral helicases is notoriously difficult to achieve, demanding alternative strategies. Here, we show that the NS3 helicase of Zika virus (ZIKV) undergoes acetylation in its RNA-binding tunnel. Regulation of the acetylated state of K389 in ZIKV NS3 modulates RNA binding and unwinding and is required for efficient viral replication. NS3 acetylation is mediated by a specific isoform of the host acetyltransferase KAT5 (KAT5γ), which translocates from the nucleus to viral replication complexes upon infection. NS3 acetylation by KAT5γ and its proviral role are also conserved in West Nile virus (WNV), dengue virus (DENV), and yellow fever virus (YFV). Our study provides molecular insight into how a cellular acetyltransferase regulates viral helicase functions, unveiling a previously unknown target for antiviral drug development.

Zika virus (ZIKV) infection is associated with the birth defect microcephaly and Guillain–Barré syndrome in adults. There is no approved vaccine or specific antiviral agent against ZIKV. ZFD-10, a novel structural skeleton of 1H-pyridazino[4,5-b]indol-4(5H)-one, was firstly synthesized and discovered to be a potent anti-ZIKV inhibitor with very low cytotoxicity. ZFD-10's anti-ZIKV potency is independent of cell lines and ZFD-10 mainly targets the post-entry stages of ZIKV life cycle. Time-of-addition and time-of-withdrawal assays showed that 10 μM ZFD-10 displayed the ability to decrease mainly at the RNA level and weakly the viral progeny particle load. Furthermore, ZFD-10 could protect ZIKV NS5 from thermal unfolding and aggregation and increase the Tagg value of ZIKV NS5 protein from 44.6 to 49.3 °C, while ZFD-10 dose-dependently inhibits ZIKV NS5 RdRp activity using in vitro RNA polymerase assays. Molecular docking study suggests that ZFD-10 affects RdRp enzymatic function through interfering with the fingers and thumb subdomains. These results supported that ZFD-10's cell-based anti-ZIKV activity is related to its anti-RdRp activity of ZIKV NS5. The in vivo anti-ZIKV study shows that the middle-dose (4.77 mg/kg/d) of ZFD-10 protected mice from ZIKV infection and the viral loads of the blood, liver, kidney and brain in the middle-dose and high-dose (9.54 mg/kg/d) were significantly reduced compared to those of the ZIKV control. These results confirm that ZFD-10 has a certain antiviral effect against ZIKV infection in vivo.

The prevalence and ravages of Zika virus (ZIKV) seriously endanger human health, especially causing significant neurological defects in both neonates as pediatric microcephaly and adults as Guillain–Barré syndrome. In this work, we studied anti-ZIKV effects of the fused tricyclic derivatives of indoline and imidazolidinone and discovered that some of them are valuable leads for drug discovery of anti-ZIKV agents. The current results show that certain compounds are broad-spectrum inhibitors of ZIKV- and dengue virus (DENV)-infection while distinctive compounds are selective ZIKV inhibitors or selective DENV inhibitors. Compounds of 12, 17 and 28 are more active against Asian ZIKV SZ-VIV01 strain than African ZIKV MR766 strain. It is valued that silylation makes six TBS compounds of 4-nitrophenyl hydrazine series and phenyl hydrazine series more active against ZIKV infection than their phenols. Time-of-addition and withdrawal studies indicate that compound 12 majorly acts on post-infection of RNA synthesis stage of ZIKV life cycle. Moreover, compounds of 12, 17 and 18 are anti-ZIKV agents with the inhibitory activities to ZIKV NS5 RdRp while 12 doesn't inhibit DENV infection even though it is a DENV RdRp inhibitor, 17 is an active agent against DENV infection but is only a weak DENV NS5 RdRp inhibitor, and 28 is inactive against DENV infection and not a DENV NS5 RdRp inhibitor. As a result, a compound's antiviral difference between ZIKV and DENV is not always related to anti-RdRp difference between ZIKV RdRp and DENV RdRp, and structural features of a compound play important roles in executing antiviral and anti-RdRp functions. Further discovery of highly potent broad-spectrum or selective agents against infection by ZIKV and DENV will be facilitated.

Infection by Zika virus (ZIKV), a mosquito-transmitted arbovirus and a member of Flavivirus, could make pediatric microcephaly and Guillain–Barré syndrome, which remains an ongoing global threat. The efficient antivirals to ZIKV infection are of great medical need. Andrographolide and its analogues were discovered to be active against flaviviral infection. In this study, we discovered some dehydroandrographolide derivatives of 3-oximido- or 3-alcohol-19-hindered ether to be potent anti-ZIKV agents with low cytotoxicities (CC₅₀ > 200 μM). Time of addition assay suggests that compound 5a and its analogues act on inhibition of post-entry stage of ZIKV life cycle. It is discovered by experimental and molecular docking studies that active anti-ZIKV compounds of 3a, 5a, 5b and 5c possess inhibitory activities of ZIKV NS5 MTase (methyl transferase) enzymatic activity. Preliminary SAR reveals that C19-modification with bulky groups is necessary for anti-ZIKV infection and replication, anti-ZIKV activity of 5a comes from itself bearing hindered trityl ether but not from its instability, the backbone of dehydroandrographolide is more effective against ZIKV infection than that of andrographolide, and 3-oxime derivatives are more active against ZIKV infection than 3-alcohol derivatives. To our knowledge, 5a is the first reported MTase inhibitor of andrographolide derivatives. More importantly, discovery of active compound 5b with acid-stable 19-OCHPh₂ against ZIKV infection is valued and gives us a clue to design and discover generally acid-stable anti-ZIKV agents.

Flavivirus and enterovirus can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases or even death. Since effective vaccine is currently unavailable against most of these deadly viruses, antiviral chemical drugs remain in urgent need. To meet this unmet demand, we developed a series of 10,10′-bis(trifluoromethyl) marinopyrrole A derivates bearing various substituents at C5′-positions, which exhibited impressive in vitro activities against flaviviruses (ZIKV, DENV, YFV, JEV) and enteroviruses (EV71, CA6, CA16). The lead compound 10,10′-bis(trifluoromethyl) marinopyrrole A 3 was highly effective against enteroviruses EV71 and CA16 in cultured cells, but with low inhibitory activities against flavivirus. Elaborately modified from compound 3, compounds 32 and 33 with sulfhydryl aliphatic chains were found as promising ZIKV and DENV inhibitor; pyrazine-containing compound 19 is a potent broad-spectrum flavivirus inhibitor; thiophene compound 15 exhibited prominent selective inhibitory effect against JEV-SA14, YFV-17D, in addition to broad-spectrum enterovirus inhibitory effect. These results thus suggest that the 5′-sulfhydryl derivates of 10,10′-bis(trifluoromethyl) marinopyrrole A may be promising lead compounds for the development of novel anti-flavivirus and anti-enterovirus drugs.