The Development of Peptide-based Antimicrobial Agents against Dengue Virus

Abstract

Dengue fever has become an imminent threat to international public health because of global warming and climate change. The World Health Organization proclaimed that more than 50% of the world's population is at risk of dengue virus (DENV) infection. Therefore, developing a clinically approved vaccine and effective therapeutic remedy for treating dengue fever is imperative. Peptide drug development has become a novel pharmaceutical research field. This article reviews various peptidesbased antimicrobial agents targeting three pathways involved in the DENV lifecycle. Specifically, they are peptide vaccines from immunomodulation, peptide drugs that inhibit virus entry, and peptide drugs that interfere with viral replication. Many antiviral peptide studies against DENV have been conducted in animal model trials, and progression to clinical trials for these promising peptide drugs is anticipated.

Keywords: Dengue fever; antimicrobial agents; clinical trials; dengue virus; peptide drug; peptide vaccine..

Fig. (1)

The lifecycle of DENV and major strategies for anti-DENV peptide drug development. The lifecycle of DENV involves complex interactions between viral proteins and host factors. Interaction begins from the E protein contacting the target host cell through receptor-mediated and clathrin-dependent endocytosis [135-138]. After internalization, viral genomic RNA is released from the endosome because the conformational change in the E protein, which is necessary for membrane fusion to occur, is triggered by pH alteration [138-140]. A single polyprotein is subsequently translated from the genomic RNA and autocatalytically cleaved into structural and nonstructural proteins through the recruitment of viral NS2B/NS3 and host proteases [25, 141]. All processed viral protein subunits are translocated to the endoplasmic reticulum (ER) membrane. Nonstructural proteins are transported to ER-derived vesicular parcels to form a replication complex, while the structural proteins prM and E are embedded into the ER membrane to enclose the nucleocapsid derived from the association of newly synthesized viral RNA with C proteins [24, 139, 142]. Subsequently, an immature viral particle is generated from the assembly of C, prM, E, and genomic RNA, and then buds into the ER-lumen to enable transport through the secretory pathway. Ultimately, the mature DENV virion is released into the cytoplasm under a low pH through furin-mediated cleavage of prM to M in the trans-Golgi network and can infect the next host cell [33, 141, 143-145]. According to the DENV lifecycle, the three major strategies for developing anti-DENV peptide drugs are immunomodulation, anti-DENV entry, and anti-DENV replication [63-99].