Fig 1.
Drugs targeting the different steps in the flavivirus life cycle.
Direct-acting antivirals*, host-targeting antivirals**, and multitarget antivirals*** that inhibit the different steps of the virus lifecycle discussed in this review are indicated in the red boxes. Flaviviruses consist of 3 structural proteins (C, prM or M, and E) and 7 NS proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), each playing distinctive roles in the different stages of the flavivirus life cycle and modulation of innate immune responses. During the virus replication cycle, the viral proteins interact with numerous host factors to modulate cellular pathways and induce infection. The flavivirus life cycle is outlined in Fig 1. (1) The E glycoprotein of the mature virion binds to the host cell membrane receptors and enters host cells via clathrin-mediated endocytosis [3]. (2) The acidic environment of the endosome triggers major structural changes in the E glycoprotein, inducing fusion of the host endosomal membrane with the viral E protein [38]. This is followed by the uncoating of the NC and the releasing of the viral genomic RNA into the cytoplasm. (3) The positive-sense viral genome (+ssRNA) is translated by ribosomes to form the viral polyprotein, which is then cleaved into structural and NS proteins by viral serine protease (NS2B-NS3) and host–cells peptidases/signalases in the ER [39]. (4) The NS proteins associate with intracellular membranes located on the surface of the ER to form viral replication complexes. The NS5 protein-derived RdRp synthesizes a complementary minus-strand RNA from genomic RNA for the synthesis of new positive-strand viral RNA [40]. (5) The newly synthesized viral RNA will then associate with the C protein in the ER to form a NC, leading to the formation of immature virions [41]. (6) Maturation and exocytosis. The assembled immature, noninfectious virion will then bud off the ER and travels through the secretory pathway to the TGN, where furin-mediated proteolysis occurs. Then, the mature virions are released from the cell surface via exocytosis [39]. C, capsid; E, envelope; ER, endoplasmic reticulum; M, membrane; NC, nucleocapsid; NS, nonstructural; prM, premembrane; RdRp, RNA-dependent RNA polymerase; TGN, trans-Golgi network.
Table 1.
Direct-acting antivirals for flaviviruses.
Table 2.
Host-targeting antivirals for flaviviruses.
Table 3.
Antiviral with multiple mechanisms of action.