Molecular characteristics and replication mechanism of dengue, zika and chikungunya arboviruses, and their treatments with natural extracts from plants: An updated review

Abstract

Viruses transmitted by arthropods (arboviruses) are the etiological agents of several human diseases with worldwide distribution; including dengue (DENV), zika (ZIKV), yellow fever (YFV), and chikungunya (CHIKV) viruses. These viruses are especially important in tropical and subtropical regions; where, ZIKV and CHIKV are involved in epidemics worldwide, while the DENV remains as the biggest problem in public health. Factors, such as, environmental conditions promote the distribution of vectors, deficiencies in health services, and lack of effective vaccines, guarantee the presence of these vector-borne diseases. Treatment against these viral diseases is only palliative since available therapies formulated lack to demonstrate specific antiviral activity and vaccine candidates fail to demonstrate enough effectiveness. The use of natural products, as therapeutic tools, is an ancestral practice in different cultures. According to WHO 80 % of the population of some countries from Africa and Asia depend on the use of traditional medicines to deal with some diseases. Molecular characteristics of these viruses are important in determining its cellular pathogenesis, emergence, and dispersion mechanisms, as well as for the development of new antivirals and vaccines to control strategies. In this review, we summarize the current knowledge of the molecular structure and replication mechanisms of selected arboviruses, as well as their mechanism of entry into host cells, and a brief overview about the potential targets accessed to inhibit these viruses in vitro and a summary about their treatment with natural extracts from plants.

Keywords: Chikungunya virus; Dengue virus; Zika virus; natural extracts; viral replication; viruses biology.

Table 1. Summary about some naturals products which has been evaluated against Flaviviruses and Alphaviruses

Figure 1. Comparison of Flavivirus and Alphavirus genome. (A) The Flavivirus, similar to the Alphavirus genus, contain single stranded RNA of positive sense; however, this has a unique open reading frame (ORF). In the 5´ end, a type I cap is present and at the 3´ end, a polyadenylation tail is observed. A typical genome has a similar order of genes and some conserved non-structural proteins (NS). (B) The viruses belonging to the Alphavirus genus possess a genome consisting of a positive sense single stranded RNA with two ORFs at the 5´ end. These code for four non-structural protein (nsP1-4). Another ORF at the 3´ end, codes for five structural proteins namely, capsid protein (C), envelope glycoproteins (E1 and E2), and two small cleavage products (E3 and 6K).

Figure 2. Life cycle of DENV in infected cells. The viral particles are released in the bloodstream; they then infect the white cells; the specific binding site of the virus is located in the E protein; it interacts with the specific superficial receptors of the host's cell, for example, mannose receptor, HSP90, HSP70, GAG heparin sulfate, DC-Sign, and TIM/TAM (Perera-Lecoin et al. 2013); this initiates the entry of the virus, endocytosis mediated by receptors is the primary route by which flavivirus are internalized. A summary of the steps that occur during the infection process from the entry of virus into the cell up to the release of new mature viral particles is as follows:

The entry into the cell is achieved by endocytosis within clathrin-coated vesicles.The acidification of endosomes leads to insertion of the E protein into the endosomal membrane, the fusion of the viral envelope, and endosomal membrane releases nucleocapsid into the cytosol. After the nucleocapsid is uncovered, the viral RNA is translated as a single polyprotein, translocated across the host endoplasmic reticulum membrane.Particles that have budded from the ER are then processed by carbohydrate addition and modification, as they proceed through the Golgi membrane system. It is likely that transportation into the trans-Golgi network requires the presence of the glycosylated prM protein. The mature viral particles are released by exocytosis and can infect more cells.

Figure 3. Life cycle of CHIKV in infected cells. The majority of the cells that get infected by CHIKV express glycosaminoglycans that apparently act as a virus-cell binding factor, increasing infectivity. Once endocytosed inside the endosome, there is a reduction in pH level. Then the endosome releases the nucleocapsid and the genome; the nsP123 precursor is translated from the viral genome and it binds to free nsP4 along with some host proteins to form the replication complex. When nsP123 concentration is enough to support an efficient reaction, it is cleaved into mature non-structural proteins: nsP1-4. These proteins together with the host cell proteins act as plus-strand RNA replicase. The 26S sub-genomic RNA encodes for the polyprotein precursor for structural proteins, which is cleaved by an autoproteolytic serine protease in order to yield C, pE2, 6K, and E1. The C and 6K proteins are accumulated in the cell's cytoplasm for the formation of new nucleocapsids. The E3, E2, and E1 proteins are glycosylated at endoplasmic reticulum and then are sent, through the Golgi apparatus, in vesicles to the cell membrane, where can interact with the nucleocapsid, resulting in the viral particles maturation to be finally released by exocytosis.