The nucleocapsid is made of multiple copies of the capsid (C) protein . The viral genome is a positive single-stranded RNA with a size of ca. 10.8 kilobases. It contains a single open reading frame (ORF) flanked by the 5' and 3' untranslated regions (UTRs) (Figure ). The ORF encodes a polyprotein precursor (3423 amino acids in length) that is post-translationally cleaved by the viral and cellular proteases into three structural proteins to produce the three structural proteins (C, PrM, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (Figure ) . The structural proteins are essential components of the virion and are involved in viral entry, fusion, and assembly, while the non-structural proteins are mainly involved in viral RNA replication, viral protein processing, and regulation of the host cell responses. NS1 is involved in viral replication, infection, and interacts with the host immune factors when secreted extracellularly for immune evasion and pathogenesis . NS3 consists of a protease domain that linked to NS2B to form a protease complex . NS5 contains RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) domains essential for viral replication, translation, and evasion of host immune response . The Zika virus protease is a serine protease with a catalytic triad formed by three residues, His51, Asp75, and Ser135, in its active site in the N-terminal region of NS3 and required a small hydrophilic proportion of NS2B as cofactor domain . The protease of ZIKV is responsible for cleaving four joints between non-structural proteins (NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5) and two sites within the C protein (C/Ci) and NS4A (NS4A/2K), which are essential to release functionally structural and non-structural proteins . Hence, inhibiting the protease activity of the Zika virus represents an important strategy in the fight against this virus. Over span of human history, naturally occurring organic chemicals were extensively used as primary treatments of a variety of medical challenges. Indeed, natural products have played central roles within drug discovery programs. Intriguingly, they display unique, diverse, and complex structural features compared to synthetic medicine, that enhance the drug discovery processes . Since 1950's, marine natural products (MNPs) and their synthetic analogues have been emerged as a revolutionary chemical space which possess unprecedented diversification of molecular articturings with novel therapeutic actions . Up to date, 17 marine derived natural products have been clinically approved as effective medications for numerous challenging diseases, whilst further 20 marine molecules are currently being investigated and developed within different clinical and preclinical phases .