Drug repositioning in the COVID-19 pandemic: fundamentals, synthetic routes, and overview of clinical studies.

INTRODUCTION: Drug repositioning is a strategy to identify a new therapeutic indication for molecules that have been approved for other conditions, aiming to speed up the traditional drug development process and reduce its costs. The high prevalence and incidence of coronavirus disease 2019 (COVID-19) underline the importance of searching for a safe and effective treatment for the disease, and drug repositioning is the most rational strategy to achieve this goal in a short period of time. Another advantage of repositioning is the fact that these compounds already have established synthetic routes, which facilitates their production at the industrial level. However, the hope for treatment cannot allow the indiscriminate use of medicines without a scientific basis. RESULTS: The main small molecules in clinical trials being studied to be potentially repositioned to treat COVID-19 are chloroquine, hydroxychloroquine, ivermectin, favipiravir, colchicine, remdesivir, dexamethasone, nitazoxanide, azithromycin, camostat, methylprednisolone, and baricitinib. In the context of clinical tests, in general, they were carried out under the supervision of large consortiums with a methodology based on and recognized in the scientific community, factors that ensure the reliability of the data collected. From the synthetic perspective, compounds with less structural complexity have more simplified synthetic routes. Stereochemical complexity still represents the major challenge in the preparation of dexamethasone, ivermectin, and azithromycin, for instance. CONCLUSION: Remdesivir and baricitinib were approved for the treatment of hospitalized patients with severe COVID-19. Dexamethasone and methylprednisolone should be used with caution. Hydroxychloroquine, chloroquine, ivermectin, and azithromycin are ineffective for the treatment of the disease, and the other compounds presented uncertain results. Preclinical and clinical studies should not be analyzed alone, and their methodology's accuracy should also be considered. Regulatory agencies are responsible for analyzing the efficacy and safety of a treatment and must be respected as the competent authorities for this decision, avoiding the indiscriminate use of medicines.

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs.

Malaria and tuberculosis are no longer considered to be neglected diseases by the World Health Organization. However, both are huge challenges and public health problems in the world, which affect poor people, today referred to as neglected populations. In addition, malaria and tuberculosis present the same difficulties regarding the treatment, such as toxicity and the microbial resistance. The increase of Plasmodium resistance to the available drugs along with the insurgence of multidrug- and particularly tuberculosis drug-resistant strains are enough to justify efforts towards the development of novel medicines for both diseases. This literature review provides an overview of the state of the art of antimalarial and antituberculosis chemotherapies, emphasising novel drugs introduced in the pharmaceutical market and the advances in research of new candidates for these diseases, and including some aspects of their mechanism/sites of action.

New Advances in General Biomedical Applications of PAMAM Dendrimers.

Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named 'starburst polymers'. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.

Dendrimer Prodrugs.

The main objective of this review is to describe the importance of dendrimer prodrugs in the design of new drugs, presenting numerous applications of these nanocomposites in the pharmaceutical field. Therefore, the use of dendrimer prodrugs as carrier for drug delivery, to improve pharmacokinetic properties of prototype, to promote drug sustained-release, to increase selectivity and, consequently, to decrease toxicity, are just some examples of topics that have been extensively reported in the literature, especially in the last decade. The examples discussed here give a panel of the growing interest dendrimer prodrugs have been evoking in the scientific community.

How do physicochemical properties contribute to inhibitory activity of promising peptides against Zika Virus NS3 protease?

CONTEXT AND RESULTS: Flavivirus diseases' cycles, especially Dengue and Yellow Fever, can be observed all over Brazilian territory, representing a great health concern. Additionally, there are no drugs available in therapy. In this scenario, in silico methodologies were applied to obtain physicochemical properties, as well as to better understand the ligand-biological target interaction mode of 20 previously reported NS2B/NS3 protease inhibitors of Dengue virus. Since catalytic site of flavivirus hold similarities, such as the same catalytic triad (His51, Asp75 e Ser135), the ability of this series of molecules to fit in Zika NS3 domains can be achieved. We performed an exploratory data analysis, using statistical methodologies, such as PCA (Principal Component Analysis) and HCA (Hierarchical Component Analysis), to assist the comprehension of how physicochemical properties impact the interaction observed by the docking studies, as well as to build a correlation between the respective ranked characteristics. Based on these previous studies, peptides were selected for the dynamics simulations, which were useful to better understand the ligand-protein interactions. Information relating to, for instance, energy, ΔG, average number of hydrogen bonds and distance from Ser135 (one of the main amino acids in the catalytic pocket) were discussed. In this sense, peptides 15 (considering ΔG value and Hbond number), 7 (ΔG and energy) and 1, 6, 7 and 15 (the proximity to Ser135 throughout the dynamics simulation) were highlighted as promising. Those interesting results could contribute to future studies regarding Zika virus drug design, since this infection represents a great concern in neglected populations. METHODS: The models were constructed in the ChemDraw software. The ligand parametrization was performed in the CHEM3D 17.0, UCSF Chimera. Docking simulations were carried out in the GOLD software, after the redocking validation. We used ASP as the function score. Additionally, for dynamics simulations we applied GROMACS software, exploring, mainly, free binding energy calculations. Exploratory analysis was carried out in Minitab 17.3.1 statistical software. Prior to the exploratory analysis, data of quantum chemical properties of the peptides were collected in Microsoft Excel spreadsheet and organized to obtain Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA).

A Review on Carbon Nanotubes Family of Nanomaterials and Their Health Field.

The use of carbon nanotubes (CNTs), which are nanometric materials, in pathogen detection, protection of environments, food safety, and in the diagnosis and treatment of diseases, as efficient drug delivery systems, is relevant for the improvement and advancement of pharmacological profiles of many molecules employed in therapeutics and in tissue bioengineering. It has contributed to the advancement of science due to the development of new tools and devices in the field of medicine. CNTs have versatile mechanical, physical, and chemical properties, in addition to their great potential for association with other materials to contribute to applications in different fields of medicine. As, for example, photothermal therapy, due to the ability to convert infrared light into heat, in tissue engineering, due to the mechanical resistance, flexibility, elasticity, and low density, in addition to many other possible applications, and as biomarkers, where the electronic and optics properties enable the transduction of their signals. This review aims to describe the state of the art and the perspectives and challenges of applying CNTs in the medical field. A systematic search was carried out in the indexes Medline, Lilacs, SciELO, and Web of Science using the descriptors "carbon nanotubes", "tissue regeneration", "electrical interface (biosensors and chemical sensors)", "photosensitizers", "photothermal", "drug delivery", "biocompatibility" and "nanotechnology", and "Prodrug design" and appropriately grouped. The literature reviewed showed great applicability, but more studies are needed regarding the biocompatibility of CNTs. The data obtained point to the need for standardized studies on the applications and interactions of these nanostructures with biological systems.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Design and exploratory data analysis of a second generation of dendrimer prodrugs potentially antichagasic and leishmanicide.

Chagas disease and leishmaniasis are neglected tropical diseases, considered as a serious public health. Also, the drugs available for their treatment are toxic and exhibit questionable efficacy. Consequently, the discovery and development of new drug candidates are currently necessary. Dendrimers are highly branched molecules with extremely controlled structure. Those molecular systems display several biological applications (i.e., drug carriers), especially when the focus is prodrug design. Herein, a second generation of dendrimer prodrugs was planned to obtain potentially antichagasic and leishmanicide delivery systems. These dendrimers were composed by myo-inositol (core), L-malic acid (spacer), and three bioactive agents [hydroxymethylnitrofurazone (NFOH), quercetin, 3-hydroxyflavone]. The major aim of this study was to investigate the molecular properties (thermodynamics, steric, steric/electronic, electronic, and hydrophobic) to further describe intersamples relationships through either similarity indices or linear combinations of the original variables. Then, an exploratory data analysis, which comprises hierarchical cluster analysis (HCA) and principal components analysis (PCA), was carried out. Complementary findings were observed for PCA and HCA. Steric, intrinsic/steric, steric/electronic, steric/hydrophobic, hydrophobic, and electronic properties influenced the discrimination process. In addition, these molecular properties can also contribute to enzymatic hydrolysis mechanism elucidation, which depends upon the approximation and a subsequent nucleophilic attack to release the drug from the dendrimer prodrugs.

Folate Pathway Inhibitors, An Underestimated and Underexplored Molecular Target for New Anti-tuberculosis Agents.

The folate metabolic cycle is an important biochemical process for the maintenance of cellular homeostasis, and is a widely studied pathway of cellular replication control in all organisms. In microorganisms such as M. tuberculosis (Mtb), for instance, dihydrofolate reductase (MtDHFR) is the enzyme commonly explored as a molecular target for the development of new antibiotics. In the same way, dihydropteroate synthase (MtDHPS) was studied extensively until the first multidrug-resistant strains of mycobacteria that could not be killed by sulfonamides were found. However, the other enzymes belonging to the metabolic cycle, until recently less explored, have drawn attention as potential molecular targets for obtaining new antituberculosis agents. Recent structural determinations and mechanism of action studies of Mtb flavin-dependent thymidylate synthase (MtFDTS) and MtRv2671, enzymes that acts on alternative metabolic pathways within the folate cycle, have greatly expanded the scope of potential targets that can be screened in drug design process. Despite the crystallographic elucidation of most cycle proteins, some enzymes, such as dihydrofolate synthase (MtDHFS) and serine hydroxylmethyltransferase (MtSHMT), remain underexplored. In this review, we highlight recent efforts towards the inhibitor design to achieve innovative antituberculosis agents and a brief history of all enzymes present in the folate metabolic cycle. In the final section of this work, we have presented the main synthetic strategies used to obtain the most promising inhibitors.

2,3-Diarylindoles as COX-2 Inhibitors: Exploring the Structure-activity Relationship through Molecular Docking Simulations.

BACKGROUND: Arylindole derivatives are promising scaffolds in the design of new drugs. These scaffolds exhibit a wide biological activity, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogen receptor modulation. OBJECTIVES: Taking this into account, this paper presents a study to understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM, on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations. METHODS: Applying molecular modelling, especially molecular docking, we assessed the SAR of a series of 2,3-arylindoles derivatives in the COX-2 enzyme. RESULTS: The results indicated that Gly 526 and Phe 381 residues are relevant for improving inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition since it enables a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring. CONCLUSION: Therefore, such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies on new selective COX-2 inhibitors.

PAMAM Dendrimers: A Review of Methodologies Employed in Biopharmaceutical Classification.

The oral route is the preferred way of drug administration for most drugs, whose treatment success is directly related to the compound intestinal absorption. This absorption process, in its turn, is influenced by several factors impacting the drug bioavailability, which is extremely dependent on the maximum solubility and permeability. However, optimizing these last two factors, without chemical structural modification, is challenging. Although poly(amidoamine) dendrimers (PAMAM) are an innovative and promising strategy as drug delivery compounds, there are few studies that determine the permeability and solubility of PAMAM-drugs derivatives. Considering this scenario, this paper aimed to carry out a literature review of the last five years concerning biopharmaceutical characterizations of dendrimer delivery systems. In vitro methodologies, such as the Parallel artificial membrane permeability assay (PAMPA) (non-cellular based model) and Caco-2 cells (cellular based model), used for the permeability evaluation in the early stages of drug discovery proved to be the most promising methodologies. As a result, we discussed, for instance, that through the usage of PAMPA it was possible to evaluate the higher capacity for transdermal delivery of DNA of TAT-conjugated PAMAM, when in comparison with unmodified PAMAM dendrimer with a P<0.05. We also presented the importance of choosing the best methods of biopharmaceutical characterization, which will be essential to guarantee the efficacy and safety of the drug candidate.

Neglected tropical diseases and systemic racism especially in Brazil: from socio-economic aspects to the development of new drugs.

Neglected tropical diseases (NTDs) are highly prevalent communicable diseases in tropical and subtropical countries, generally not economically attractive for drug development and related to poverty. In Brazil, more specifically, socioeconomic inequalities and health indicators are strongly influenced by skin color, race, and ethnicity, due to the historical process of slavery. In this context, it is important to understand the concept of systemic racism: a form of indirect racial discrimination present in many institutions, which determines the process of illness and death of the black population, the ethnic group most affected by these diseases. The main objective of this paper was to carry out a literature review on the socioeconomic aspects of these diseases, relating them to institutional racism, and to encourage reflection on the influence of this type of racism in the NTDs context. Therefore, we present a paper that brings a evident correlation between racism versus neglected populations, which are affected by equally neglected diseases. A more humane and comprehensive view is needed to realize that these illnesses affect neglected and vulnerable populations, who require decent living conditions, health, and social justice. We hope to provide, with this paper, enough, but not exhaust, knowledge to initiate the discussion about neglected diseases, their socioeconomic aspects and institutional racism.

Zika Virus NS2B-NS3 Protease: Quantum Chemical Properties Insights into Designing Inhibitory Peptides.

BACKGROUND: Zika fever affects poor and vulnerable populations, presenting cycles observed in, at least 86 countries, with no vaccine prevention or treatment available. It is known that the genus Flavivirus causes Zika Virus (ZIKV), as Dengue and Yellow Fever, whose genetic material decodes, among other proteins, a series of non-structural (NS) proteins essential for viral replication, such as NS2B-NS3 protease. Additionally, chemical and biological systems are commonly studied using molecular modeling approaches allowing, among several other processes, to elucidate mechanisms of action, molecule reactivity and/or chemical properties and the design of new drugs. Thus, considering the in silico complexes between the biological target and the bioactive molecule, it is possible to understand better experimental results based on molecular properties, which are compared with the findings of the biological activity. OBJECTIVE: Accordingly, this study aimed to present computational docking simulations of five previously reported active peptides against NS2B-NS3 protease of ZIKV and analyze some quantum chemical properties to identify the main contribution to improving the action. METHODS: The compounds were described by Rut and coworkers (2017) and Hill and coworkers (2018), submitted to docking simulation in Gold software and quantum chemical properties calculations in Wavefunction Spartan software. RESULTS: Total energy, electrophilicity index (ω) and energy gap (GAP) appeared to be the best properties to justify the peptide's biological activity. Moreover, the most promising compound (P1, Km 4.18 µM) had the best value of total energy (- 2763.04001 au), electrophilicity index (8.04 eV) and GAP (6.49 eV), indicating an energetically favorable molecule with good interaction with the target and, when compared to other peptides, presented moderate reactivity. P4 showed the highest electrophilicity index value (28.64 eV), which justified the interaction ability visualized in the docking simulation. However, its GAP value (4.24 eV) was the lowest in the series, suggesting high instability, possibly validating its low biological activity value (Km 19 uM). GAP was important to understand the chemical instability, and high values can promote damage to biological response. CONCLUSION: Furthermore, it was also noted that high electron affinity, related to the electrophilicity index, promoted electron-accepting characteristics, which was important to improve the biological activity of the peptides. A larger compound series must be studied to access features more precisely. However, these results have paramount importance in guiding future effort in this extremely-need health area.

Resveratrol and Curcumin for Chagas Disease Treatment-A Systematic Review.

Chagas disease (CD) is a neglected protozoan infection caused by Trypanosoma cruzi, which affects about 7 million people worldwide. There are two available drugs in therapeutics, however, they lack effectiveness for the chronic stage-characterized mainly by cardiac (i.e., cardiomyopathy) and digestive manifestations (i.e., megaesophagus, megacolon). Due to the involvement of the immuno-inflammatory pathways in the disease's progress, compounds exhibiting antioxidant and anti-inflammatory activity seem to be effective for controlling some clinical manifestations, mainly in the chronic phase. Resveratrol (RVT) and curcumin (CUR) are natural compounds with potent antioxidant and anti-inflammatory properties and their cardioprotective effect have been proposed to have benefits to treat CD. Such effects could decrease or block the progression of the disease's severity. The purpose of this systematic review is to analyze the effectiveness of RVT and CUR in animal and clinical research for the treatment of CD. The study was performed according to PRISMA guidelines and it was registered on PROSPERO (CDR42021293495). The results did not find any clinical study, and the animal research was analyzed according to the SYRCLES risk of bias tools and ARRIVE 2.0 guidelines. We found 9 eligible reports in this study. We also discuss the potential RVT and CUR derivatives for the treatment of CD as well.

Vaccinium myrtillus L. extract associated with octocrylene, bisoctrizole, and titanium dioxide: in vitro and in vivo tests to evaluate safety and efficacy.

OBJECTIVE: The harmful effects induced by ultraviolet exposition and the significant increment in skin cancer diagnosis confirm the necessity to develop effective and safe sunscreens. Limited efficacy and cutaneous adverse reactions of traditional formulations drove the incorporation of natural extracts into multifunctional sunscreens. Vaccinium myrtillus L. extract (VME), that contains anthocyanins and flavonoids, is a potential candidate for such systems. METHODS: Considering that, we performed in vitro and in vivo tests to evaluate the sun protection factor (SPF), photostability, and safety of sunscreen samples containing VME. RESULTS: As main results, the SPF was reduced in both in vitro and in vivo evaluation in the presence of VME; nonetheless, the samples were photostable and safe. CONCLUSION: Further investigation is required to better understand the unexpected effects of VME over photoprotection, decreasing the SPF value. As a conclusion, even with interesting findings, we highlight the importance of case-by-case investigations to develop multifunctional bioactive sunscreens.

Analytical Quality by Design as an Important Tool to Determine the Best Analytical Conditions for Isoniazid and Its Respective Succinylated Prodrug.

BACKGROUND: Tuberculosis is a worldwide health concern and isoniazid is the most used and considered one of the most effective drugs for its treatment. The "quality" concept must be incorporated into the final pharmaceutical product, according to the quality by design (QbD) definition. Therefore, the determination of analytical test conditions is extremely important and the design of experiments (DoE) becomes a very useful tool. OBJECTIVE: This paper used the concept of QbD to assist the development of analytical conditions for isoniazid and its respective prodrug, applying HPLC. METHOD: HPLC analytical methodologies were developed for isoniazid and its succinylated derivative. The experimental design was carried out using three analytical parameters at three levels. Four chromatographic responses were studied. The impact of analytical parameters on chromatographic responses was assessed using a Pareto chart. Regression models were obtained using multiple regression analysis. DoE analysis was conducted using the Minitab® program and the experiments were performed sequentially, with varying factors. RESULTS: We identify three main risk parameters: mobile phase (high), flow rate (moderate), and pH of buffer (moderate). The ratio of mobile phase buffer (X2) and mobile phase pH (X3) had a major influence on the peak resolutions (Y3). The capacity factors for iso-suc (Y1) and isoniazid (Y2) peaks should be within 3-9 and 4-10, respectively. The peak resolutions between iso-suc and isoniazid (Y3) should be above two. CONCLUSIONS: We designed 27 experiments, obtaining 1.0 mL/min flow rate, 95% buffer in the mobile phase, and pH 7.0 as the optimal analytical conditions. HIGHLIGHTS: Analytical Quality by Design was used as an important tool to determine the best analytical test conditions for isoniazid and its respective prodrug - succinylated isoniazid.

Neglected tropical diseases and infectious illnesses: potential targeted peptides employed as hits compounds in drug design.

Neglected Tropical Diseases (NTDs) and infectious illnesses, such as malaria, tuberculosis and Zika fever, represent a major public health concern in many countries and regions worldwide, especially in developing ones. They cause thousands of deaths per year, and certainly compromise the life of affected patients. The drugs available for therapy are toxic, have considerable adverse effects, and are obsolete, especially with respect to resistance. In this context, targeted peptides are considered promising in the design of new drugs, since they have specific action and reduced toxicity. Indeed, there is a rising interest in these targeted compounds within the pharmaceutical industry, proving their importance to the Pharmaceutical Sciences field. Many have been approved by the Food and Drug Administration (FDA) to be used as medicines, plus there are more than 300 peptides currently in clinical trials. The main purpose of this review is to show the most promising potential targeted peptides acting as hits molecules in NTDs and other infectious illnesses. We hope to contribute to the discovery of medicines in this relatively neglected area, which will be extremely useful in improving the health of many suffering people.

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties.

Hydroxymethylation is a simple chemical reaction, in which the introduction of the hydroxymethyl group can lead to physical-chemical property changes and offer several therapeutic advantages, contributing to the improved biological activity of drugs. There are many examples in the literature of the pharmaceutical, pharmacokinetic, and pharmacodynamic benefits, which the hydroxymethyl group can confer to drugs, prodrugs, drug metabolites, and other therapeutic compounds. It is worth noting that this group can enhance the drug's interaction with the active site, and it can be employed as an intermediary in synthesizing other therapeutic agents. In addition, the hydroxymethyl derivative can result in more active compounds than the parent drug as well as increase the water solubility of poorly soluble drugs. Taking this into consideration, this review aims to discuss different applications of hydroxymethyl derived from biological agents and its influence on the pharmacological effects of drugs, prodrugs, active metabolites, and compounds of natural origin. Finally, we report a successful compound synthesized by our research group and used for the treatment of neglected diseases, which is created from the hydroxymethylation of its parent drug.

Future and Perspectives of the Zika Virus: Drug Repurposing as a Powerful Tool for Treatment Insights.

The Zika virus (ZIKV) infection is a major public health concern in Brazil and worldwide, being a rapidly spreading disease with possible severe complications for pregnant women and neonates. There is currently no preventative therapy or specific treatment available. Within this context, drug repositioning is a very promising approach for the discovery of new treatment compounds, since old drugs may become new ones. Therefore, this paper aims to perform a literature mini-review to identify promising compounds to combat this virus. The mechanism of action at the molecular level and the structure-activity relationship of prototypes are discussed. Among the candidates identified, we highlight sofosbuvir, chloroquine and suramin, which present a greater quantity of experimental data to draw on for our discussion. The current treatment is palliative; therefore, this study is of paramount importance in identifying drug candidates useful for combating ZIKV.