REVIEW ARTICLE

A Narrative Review on Current Development and Future Prospects for the Treatment of Dengue Virus Infection

Abstract

Incidences of dengue-virus infection are increasing globally. Around 3.90 billion population is at high risk of infection. There is no cure/ prevention available. Hence aim of the current review was the evaluation of current development and prospects for the production of safe anti-dengue drugs. The data of review was synthesized by PRISMA. Grading of Recommendation Assessment, Development, and Evaluation criteria were employed to establish the quality of the literature. Many drugs/compounds have shown promising prospects. Target site of these drugs on dengue virus were inhibition of replication (N-sulfonyl peptide-hybrids, milk-exosomes, sunitinib, schisandrin-A, cavinafungin, minocycline, 4-hydroxyphenyl retinamide, Goniothalamus umbrosus, Dryopteris crassirhizoma, Morus alba, statins), protease-enzyme (Thiazolidinone-peptide, nelfinavir, carnosine, 1,2-benzisothiazol-3(2H)- one and 1,3,4-oxadiazole), capsid-protein (Juglanin and silymarin), NS4B-gene (Desatinib), entry-in-host-cell (Duramycin, glycodendrimers, curdlan sulfate), RNA-capping (Lanatoside-C), fusion (Chloroquine) and NS3-helicase (Suramina). Many compounds/drugs are found effective by targeting the structural proteins of the dengue virus to use as a therapy in the future.

Keywords: Dengue infection, virus replication, fusion, capsid, NS3 helicase, protease, treatment.

INTRODUCTION

Burden of Infection: It is a bleak reality that in the last few decades; cases of dengue infection have increased frequently and up to 30% of incidences are reported worldwide [1]. Globally deaths of the majority of individuals occurred due to dengue infection in urban areas; therefore, it is found that most dengue fever cases have a linkage with urbanization [2]. It is also noted that the antibody-dependent enhancement (ADE) effect raises the risk of mortality in second exposure to dengue viral infections; it is perhaps due to the complex formation between dengue virus and non-neutralizing antibodies and prevents phagocytosis of the virus by immune cells [3]. ADE is the first time reported in clinical trials of dengue virus vaccine [4]. Pakistan is located in a subtropical region geographically; faced abrupt cases of dengue infection across the major cities in 2005, with about 257 deaths reported in the city of Lahore due to dengue fever in 2021 [5]. Historically, the first dengue fever observed in Madras, India in 1780; while first reported endemic dengue fever situation was existed in India during 1963-1964, in Calcutta and coastal areas of India towards the Eastern side [6].

Dengue Virus: Dengue infection is one the vector born infection; mostly found in humid and sub-humid zones including Pakistan [7]. The dengue virus belongs to the flavivirus family; having four serotypes DEN-1, DEN- 2, DEN-3, and DEN-4 [8]. It is a single-stranded RNA

(Robinucleic acid) virus and contains 10,700 bases [9]. Transmission of dengue virus infection is mainly due to female mosquito species (Aedes aegypti and Aedes albopictus) [10]. Unfortunately, the dengue viral infection is responsible for a high mortality rate in individuals across the globe [11]. The incubation period experienced by most infected persons is about 2-7 days [12]. The disease is sometimes asymptomatic as well as symptomatic, clinical symptoms include; pyrexia, dizziness due to loss of blood in case of hemorrhagic fever (HF), extreme fatigue, skin rashes, muscular tightness, pain in the whole body, throat infection and decreased level of hemoglobin [13]. Study shows that dengue infection is responsible for multiple organ failure with different clinical manifestations; ultimately resulting in the death of individuals if not managed properly [14]. The guideline (1997) of the World Health Organization shows the categorization of infected people due to dengue infection as; simple dengue infection, complicated infection due to internal bleeding, and anaphylactic shock disorder [15]. Clinical diagnosis of dengue is possible by numerous modern techniques; using genetic modeling of the dengue virus, detection of antibodies of anti-dengue virus, and by using non- structural (NS1) antigen [16].

Classical Dengue Fever: Dengue hemorrhagic fever is a classical dengue fever. It has four clinical manifestations; high grade fever, hemorrhages, sometimes hepatomegaly, and circulatory failure [4]. Some individuals with dengue hemorrhagic fever may develop hypovolemic shock [17]. This fever is reported in many countries in Asia and the Pacific Island; the mechanism is still not well understood yet, however, some

Liaquat National Journal of Primary Care 2024; 6(2): 165-173 ISSN: 2708-9134 (Online) (All articles are published under the Creative Commons Attribution License) 165

Sheikh Abdul Khaliq, Muneer Khan, Saquib Azeem and Anab Fatima

hypothesis suggests risk factors for the development of dengue hemorrhagic fever e.g. virulence of the virus, a storm of cytokines, autoimmune response and genetic factor of host cells [4]. Another classical fever is dengue shock syndrome. Dengue shock syndrome is more severe than dengue hemorrhagic fever; in this clinical situation, patients may have bleeding, pleural effusion, leakage of plasma, pain in the abdomen, thrombocytopenia, hypotension, impairments of vital organs, cardiac arrest and/or cardiopulmonary failure [4]. Due to the severity of dengue hemorrhagic fever and dengue shock syndrome, early detection of infection is required for optimum treatment and to get desirable clinical outcomes [4].

Treatment of Infection: The point of concern is that there is no proper treatment against dengue virus infection either suitable antiviral or immune-therapeutics [18]. Since there is no systematic treatment for dengue; some antibiotics and anti-inflammatory drugs are commonly used to moderate the symptoms caused by secondary microbial infections, such as tetracycline derivatives and non-steroidal anti-inflammatory drugs (NSAIDs) [19]. Normally infection recovery is possible within 4 to 9 days [20]. The use of natural sources was found scientifically beneficial against dengue infection-induced thrombocytopenia. Recently extract or juice from Carica papaya gained attraction for the potential use in dengue infection control by increasing platelet counts [21]. Another study revealed that the derivatives of phenolthiazine and trifluoperazine (TFP) are found successful in restricting the growth of flavivirus by showing antiviral mechanisms against all four serotypes of dengue viruses [22]. Literature reported several compounds as direct-acting anti-viral and host- directed anti-viral drugs for the treatment; however, none is established yet as a promising drug [23]. World Health Organization reports show that environmental management effectively contributes to the control of dengue viral infection; climate change, abrupt modifications in the environment, lifestyle changes, proper treatment of waste from different sources, use of adequate natural resources, storage container mechanisms to limit mosquitoes access, proper fumigation schedule and enlighten infrastructure may reduce the burden of infection [24]. The global population is constantly facing risks of emerging infectious diseases [25]. Around the world; the key focus goal is to produce a safe and effective vaccine against dengue infection. One of the recognized registered vaccines in some countries of the world is Dengvaxia®; however, it is used with some limitations [18]. The strategic approach of the World Health Organization for 2021-2030 is to minimize, control, treat, and/or eradicate the dengue infection fatal outcome rate to 0% [26].

Objective of Review: The objective and intention of the current review are to mainly focus on and evaluate the

current development and prospects for the production of safe anti-dengue viral drugs, therapy, and measures to control.

METHODOLOGY

To write a narrative review on the topic of current development and prospects for dengue control; a literature survey was conducted from 2013 to 2023 by two authors. Key-words and truncation techniques were used for the collection of relevant literature from PubMed, Directory of Open Access Journals (DOJA), BioMed Central, Google Scholar, PakMediNet, National Database of Indian Medical Journals, African Journals Online (AJOL), Bioline International and Emerald. Eighty articles on the said topic were downloaded; seventy- seven were chosen after abstracting relevant information from the studies and assessing quality, data synthesized and presented by following the PRISMA flow diagram (Fig. 1) [27]. The PRISMA diagram details how studies were identified, the results of abstract screening, the results of full-text eligibility assessment; the breakdown of reasons for exclusion, and details of included studies [28]. Full-text eligible articles were sixty. All the articles were evaluated for their quality, type of journal, data collection methods, statistical tests, significance values, and interpretations made.

Quality of Literature Evaluation: GRADE (Grading of Recommendation Assessment, Development and Evaluation) criteria were employed for establishing the quality of literature. GRADE is an explicit and transparent system for decision-making regarding the best available literature [29].

Evidence/Literature Inclusion Criteria: Evidence about the dengue virus, infection, prevalence, its current modes of treatments, and new developments. Literature published from 2013 to 2023.

Evidence/Literature Exclusion Criteria: Literature reported the cases of co-morbid or multiple infections, un-confirmed diagnosis of dengue infection, and literature published before 2013.

FINDINGS AND RESULTS OF REVIEW

Reported compounds and drugs acted against dengue virus by different mechanisms (Table 1).

Table 1: Compounds and drugs acted against dengue virus replication.

DISCUSSION

It is a bleak reality that no anti-viral drug is currently licensed anywhere around the world against flavivirus; which is causing a significant burden of diseases, particularly Dengue virus. Dengue is very common nowadays and transmitted by the bite of Aedes aegypti, a female vector that influences more than 20% population every year across the world [72]. One-third of the world’s population has concerns about dengue infection propagation which is alarming for health safety [73]. The incidences of dengue infections have increased up to 30 times within the last few decades [74]. It is noteworthy that the age factor also contributes to dengue infection incidences; people under the age of 14 and above 70 years are more susceptible to infection [75]. Dengue infection is a febrile infection and if not managed properly in time; leads to severe complications, especially in children [76]. Climate changes have strong consequences for the spreading of dengue infection across the globe. Humid and sub-humid regions, hot climatic regions having strong rainfall are favorable environments for vector growth and propagation of dengue virus. That is why climate sensitivity is an important parameter contributing to the successful growth and multiplication of parasites and miniatures [77]. Transmission of dengue infection by the flavivirus family through a complicated cycle from infected person to healthy people repeated very rapidly and is a main cause of the spread of infection worldwide [77]. The incubation period for an acute dengue infection is typically three to fourteen days. It can range from asymptomatic to life-threatening. The illness can also be categorized into three phases; critical, febrile, and recovery. The critical phase lasts for about three to seven days [78]. Fever, which can reach over 40 degrees Celsius usually appears within two to seven days. It can be accompanied by various symptoms such as nausea, vomiting, abdominal pain, and lymphadenopathy [78]. Due to the severity of the dengue infection in infected people, it can lead to gene expression at multiple levels [78].

Severe dengue infection can only managed by supportive therapy, which includes excessive administration of intra- venous fluid and painkillers particularly Acetaminophen to reduce the complications and to avoid unbearable loss of fluid in case of vascular porosity [72]. From the current review, it is revealed that structural proteins have a key role in the propagation of viruses, enhance entry chances, and assemble and secrete friendly chemicals for viral attachment; on the other hand, the non- structural viral proteins are vital for immunity of virus, its propagation and enzyme enhancement [79]. The presence of non-structural ( NS1) protein in the body fluid is the main contributor to detecting the presence of dengue virus and thus helpful in effective diagnosis [80]. Many drugs are studied by targeting these proteins of the dengue virus to use as a therapy for dengue infection [39, 52, 58, 81, 82]. Natural resources are the best for humanity for the ailment of various infections.

It has been observed in current study that dengue virus growth is inhibited by various mechanisms; these mechanisms include inhibition of replication by interaction with different viral ribosomal proteins [22, 30, 33, 34, 45, 48, 50, 55, 56, 61], viral protease enzyme inhibition, which is necessary for ribosomal proteins synthesis of virus [31, 45, 58, 63], termination of RNA

chain [32, 68], inhibition of viral envelop proteins [35], antagonism of dopamine 2 receptor [36] to arrest viral nervous system, Activation of AMP-activated protein kinases and reduction of 3-hydroxy-3-methylglutaryl- coenzyme-A reductase activity [38] and hence interfere with the metabolic activity of virus, SIRT1/2 (Sirtuins) inhibition [39] to produce neurodegenerative effect on virus, inhibition of virus binding and entry in host cells [44, 46, 64, 66, 71], inhibition of NS4B gene of virus which is necessary for its growth [52, 70], accumulation of alpha glucosidase enzyme [54] to suppress glucose metabolism of virus, inhibition of NS3 helicase of virus [57, 62, 69], inhibition of viral fusion with host cell membrane and maturation and generation of free heme [60, 67]. All of these mechanisms are about viral growth and replication. Interaction of these drugs may not only produce virustatic activity but also viricidal. The ultimate goal is clinical improvement against infection, which needs further research in human beings, as most of the studies are conducted either on animals or on in-vitro cell lines.

Primary natural resource such as plants plays a vital role in biodiversity to control diseases. Uptakes of fresh citrus juices and extract of papaya leaves [33] from natural sources are the best remedies temporarily during dengue infection particularly for the management of thrombocytopenia [40, 42, 43, 83, 84]. With the emergence of new infectious diseases, it is becoming difficult to develop and produce urgent, effective, safe, and potential vaccines or therapeutic agents. Currently, only one live attenuated tetravalent chimeric vaccine made by recombinant DNA technology is registered in some countries [85]. This vaccine provides long-term protection in single or multiple doses [85]. In clinical studies, it has been observed that the vaccine is more effective in individuals above 9 years old [86]. The main limitation of this vaccine is the risk of hospitalization, as observed in a 3-year long-term safety assessment [87]. In addition to live attenuated vaccines; some other vaccines are also under investigation against dengue virus infection, these vaccines include; DNA vaccines, inactivated vaccines, and recombinant sub-unit vaccines [3]. Similarly, there is no proper treatment protocol for the cure and management of dengue infection. In severe cases only temporary measurements can be taken to reduce the severity of infection; e.g. fluid therapy and the use of painkillers [88]. Prophylactic vaccination for high-risk populations against dengue fever is one of the rational tools to reduce the burden of infection globally. In addition, Muslim societies across the globe are very sensitive to halal incipients and excipients of

anti-dengue drugs or vaccines and other infections vaccines [89]. Unfortunately, to date, no efficacious and safe vaccine is available to reduce the rate of dengue cases below 1% in such a modernized and technical era [72]. Different studies have shown that the main reasons for the failure to develop an effective vaccine or drug against the dengue virus are; changes in structure, shape, genetic variations or recombination, diversified genome, virulence and specification for host attachment, susceptibility due to climatic diversity of flavivirus family [73].

LIMITATIONS AND CHALLENGES

The main limitation of the current review is that most of the studies are conducted either in animals as an experimental study or in-vitro cell lines, clinical data of these compounds are limited against dengue virus infection. In addition, some compounds which have shown activity against dengue viruses are already in clinical use for different therapeutic indications;

e.g. Dasatinib, Lovastatin, Chloroquine, Duramycin, Nelfinivir, Minocycline, Sunitinib, Erlotinib, Orlistat, Metformin, Metoclopramide and Trifluoperazine. These compounds will not be acceptable for the treatment of dengue infection in clinical practice unless standardized randomized clinical trials with clear end-points are available for their efficacy and safety. The in-vitro activities against different serotypes of dengue viruses of these compounds are creating another challenge for Pharmaceutical and Biomedical scientists. These challenges include the formulation of safe, effective, stable, tolerable, and practical dosage forms. It is also noted in some studies that many drugs are effective when used in vitro, but when used in vivo, they lose their efficacy.

CONCLUSION

Dengue fever spread out as an endemic worldwide; which badly affects the health of the population of the tropical and subtropical regions. It is a major public health issue across the globe. The main contributing factors to the transmission of the dengue virus are climate change, human lifestyle, bad sanitary system, evolution in viral genetics, socioeconomic factors, devastating urbanization, uncontrolled population, and global travel and trade mechanisms. Researchers have not yet succeeded in developing any therapeutic entity or safe vaccine against dengue infection. Some natural sources are contributed to minimize the complications of dengue infection, e.g. fresh juice from citrus fruits and extract of Carica papaya. A study also reveals the effectiveness of phenothiazine derivative (Trifluoperazine) against all serotypes of dengue viruses.

RECOMMENDATIONS

The world is still facing outbreaks of dengue infection. Hence continuous efforts in the area of research are required to develop either anti-dengue therapy or a

cost-effective and safe vaccine. It is suggested that the development of recombinant, live-attenuated dengue vaccine against all serotypes of dengue viruses may be safe, protective, and tolerable. Based upon the current review, it is observed that using modern techniques and technologies such as x-ray modeling, screening methodologies, and accessible databases will provide sound groundwork to develop unique antiviral therapeutic agents against dengue infection. At the moment the best approaches or strategies to prevent dengue infection are; avoiding contact with infected people, avoiding mosquito-rich areas, using proper insecticides, covering exposed body parts, changing living lifestyle, monitoring climate changes worldwide, and suitable precautionary measures.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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