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1.
ACS Infect Dis ; 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38992989

ABSTRACT

The Alphavirus genus includes viruses that cause encephalitis due to neuroinvasion and viruses that cause arthritis due to acute and chronic inflammation. There is no approved therapeutic for alphavirus infections, but significant efforts are ongoing, more so in recent years, to develop vaccines and therapeutics for alphavirus infections. This review article highlights some of the major advances made so far to identify small molecules that can selectively target the structural and the nonstructural proteins in alphaviruses with the expectation that persistent investigation of an increasingly expanding chemical space through a variety of structure-based design and high-throughput screening strategies will yield candidate drugs for clinical studies. While most of the works discussed are still in the early discovery to lead optimization stages, promising avenues remain for drug development against this family of viruses.

2.
Eur J Med Chem ; 263: 115954, 2024 Jan 05.
Article in English | MEDLINE | ID: mdl-37984297

ABSTRACT

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense and rhodesiense, is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth of T. b. brucei, T. b. gambiense and T. b. rhodesiense, have excellent oral bioavailability and was effective in treating acute infection of HAT in mouse models. Based on its excellent bioavailability, compound 10 and its analogs are candidates for lead optimization and pre-clinical investigations.


Subject(s)
Trypanocidal Agents , Trypanosoma brucei brucei , Trypanosomiasis, African , Animals , Mice , Humans , Trypanosoma brucei rhodesiense , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitology , Trypanosoma brucei gambiense
3.
PLOS Glob Public Health ; 3(7): e0001935, 2023.
Article in English | MEDLINE | ID: mdl-37467165

ABSTRACT

The lack of routine viral genomic surveillance delayed the initial detection of SARS-CoV-2, allowing the virus to spread unfettered at the outset of the U.S. epidemic. Over subsequent months, poor surveillance enabled variants to emerge unnoticed. Against this backdrop, long-standing social and racial inequities have contributed to a greater burden of cases and deaths among minority groups. To begin to address these problems, we developed a new variant surveillance model geared toward building 'next generation' genome sequencing capacity at universities in or near rural areas and engaging the participation of their local communities. The resulting genomic surveillance network has generated more than 1,000 SARS-CoV-2 genomes to date, including the first confirmed case in northeast Louisiana of Omicron, and the first and sixth confirmed cases in Georgia of the emergent BA.2.75 and BQ.1.1 variants, respectively. In agreement with other studies, significantly higher viral gene copy numbers were observed in Delta variant samples compared to those from Omicron BA.1 variant infections, and lower copy numbers were seen in asymptomatic infections relative to symptomatic ones. Collectively, the results and outcomes from our collaborative work demonstrate that establishing genomic surveillance capacity at smaller academic institutions in rural areas and fostering relationships between academic teams and local health clinics represent a robust pathway to improve pandemic readiness.

4.
Molecules ; 28(9)2023 Apr 25.
Article in English | MEDLINE | ID: mdl-37175100

ABSTRACT

Natural products (NPs) from plants, fungi, animals, and microorganisms have historically played important roles in drug discovery [...].


Subject(s)
Biological Products , Animals , Biological Products/pharmacology , Biological Products/therapeutic use , Drug Discovery , Fungi , Plants
5.
Planta ; 257(4): 78, 2023 Mar 13.
Article in English | MEDLINE | ID: mdl-36913066

ABSTRACT

MAIN CONCLUSION: The enhancement of CRISPR-Cas gene editing with robust nuclease activity promotes genetic modification of desirable agronomic traits, such as resistance to pathogens, drought tolerance, nutritional value, and yield-related traits in crops. The genetic diversity of food crops has reduced tremendously over the past twelve millennia due to plant domestication. This reduction presents significant challenges for the future especially considering the risks posed by global climate change to food production. While crops with improved phenotypes have been generated through crossbreeding, mutation breeding, and transgenic breeding over the years, improving phenotypic traits through precise genetic diversification has been challenging. The challenges are broadly associated with the randomness of genetic recombination and conventional mutagenesis. This review highlights how emerging gene-editing technologies reduce the burden and time necessary for developing desired traits in plants. Our focus is to provide readers with an overview of the advances in CRISPR-Cas-based genome editing for crop improvement. The use of CRISPR-Cas systems in generating genetic diversity to enhance the quality and nutritional value of staple food crops is discussed. We also outlined recent applications of CRISPR-Cas in developing pest-resistant crops and removing unwanted traits, such as allergenicity from crops. Genome editing tools continue to evolve and present unprecedented opportunities to enhance crop germplasm via precise mutations at the desired loci of the plant genome.


Subject(s)
CRISPR-Cas Systems , Crops, Agricultural , Plant Breeding , CRISPR-Cas Systems/genetics , Crops, Agricultural/genetics , Gene Editing , Genome, Plant/genetics , Mutagenesis, Site-Directed , Plants, Genetically Modified/genetics
6.
bioRxiv ; 2022 Oct 20.
Article in English | MEDLINE | ID: mdl-36299431

ABSTRACT

The lack of routine viral genomic surveillance delayed the initial detection of SARS-CoV-2, allowing the virus to spread unfettered at the outset of the U.S. epidemic. Over subsequent months, poor surveillance enabled variants to emerge unnoticed. Against this backdrop, long-standing social and racial inequities have contributed to a greater burden of cases and deaths among minority groups. To begin to address these problems, we developed a new variant surveillance model geared toward building microbial genome sequencing capacity at universities in or near rural areas and engaging the participation of their local communities. The resulting genomic surveillance network has generated more than 1,000 SARS-CoV-2 genomes to date, including the first confirmed case in northeast Louisiana of Omicron, and the first and sixth confirmed cases in Georgia of the emergent BA.2.75 and BQ.1.1 variants, respectively. In agreement with other studies, significantly higher viral gene copy numbers were observed in Delta variant samples compared to those from Omicron BA.1 variant infections, and lower copy numbers were seen in asymptomatic infections relative to symptomatic ones. Collectively, the results and outcomes from our collaborative work demonstrate that establishing genomic surveillance capacity at smaller academic institutions in rural areas and fostering relationships between academic teams and local health clinics represent a robust pathway to improve pandemic readiness. Author summary: Genomic surveillance involves decoding a pathogen’s genetic code to track its spread and evolution. During the pandemic, genomic surveillance programs around the world provided valuable data to scientists, doctors, and public health officials. Knowing the complete SARS-CoV-2 genome has helped detect the emergence of new variants, including ones that are more transmissible or cause more severe disease, and has supported the development of diagnostics, vaccines, and therapeutics. The impact of genomic surveillance on public health depends on representative sampling that accurately reflects the diversity and distribution of populations, as well as rapid turnaround time from sampling to data sharing. After a slow start, SARS-CoV-2 genomic surveillance in the United States grew exponentially. Despite this, many rural regions and ethnic minorities remain poorly represented, leaving significant gaps in the data that informs public health responses. To address this problem, we formed a network of universities and clinics in Louisiana, Georgia, and Mississippi with the goal of increasing SARS-CoV-2 sequencing volume, representation, and equity. Our results demonstrate the advantages of rapidly sequencing pathogens in the same communities where the cases occur and present a model that leverages existing academic and clinical infrastructure for a powerful decentralized genomic surveillance system.

7.
Molecules ; 27(18)2022 Sep 15.
Article in English | MEDLINE | ID: mdl-36144741

ABSTRACT

Carotenoids are isoprenoid-derived natural products produced in plants, algae, fungi, and photosynthetic bacteria. Most animals cannot synthesize carotenoids because the biosynthetic machinery to create carotenoids de novo is absent in animals, except arthropods. Carotenoids are biosynthesized from two C20 geranylgeranyl pyrophosphate (GGPP) molecules made from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the methylerythritol 4-phosphate (MEP) route. Carotenoids can be extracted by a variety of methods, including maceration, Soxhlet extraction, supercritical fluid extraction (SFE), microwave-assisted extraction (MAE), accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), pulsed electric field (PEF)-assisted extraction, and enzyme-assisted extraction (EAE). Carotenoids have been reported to exert various biochemical actions, including the inhibition of the Akt/mTOR, Bcl-2, SAPK/JNK, JAK/STAT, MAPK, Nrf2/Keap1, and NF-κB signaling pathways and the ability to increase cholesterol efflux to HDL. Carotenoids are absorbed in the intestine. A handful of carotenoids and carotenoid-based compounds are in clinical trials, while some are currently used as medicines. The application of metabolic engineering techniques for carotenoid production, whole-genome sequencing, and the use of plants as cell factories to produce specialty carotenoids presents a promising future for carotenoid research. In this review, we discussed the biosynthesis and extraction of carotenoids, the roles of carotenoids in human health, the metabolism of carotenoids, and carotenoids as a source of drugs and supplements.


Subject(s)
Biological Products , Carotenoids , Animals , Biological Products/pharmacology , Carotenoids/metabolism , Cholesterol , Diphosphates/metabolism , Drug Discovery , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Plants/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Solvents , TOR Serine-Threonine Kinases/metabolism , Terpenes/metabolism
8.
RSC Adv ; 12(18): 11346-11375, 2022 Apr 07.
Article in English | MEDLINE | ID: mdl-35425061

ABSTRACT

Plant-based secondary metabolites have been a major source of drug discovery and inspiration for new generations of drugs. Plants offer a wide variety of compound classes, including alkaloids, terpenes, flavonoids, and glycosides, with different molecular architectures (fused bridgehead, bi- and polycyclic, spirocyclic, polycyclic, and acyclic). The diversity, abundance, and accessibility of plant metabolites make plants an attractive source of human and animal medicine. Even though the pinene scaffold is abundant in nature and has historical use in traditional medicine, pinene and pinene-derived compounds have not been comprehensively studied for medicinal applications. This review provides insight into the utility of the pinene scaffold as a crucial building block of important natural and synthetic products and as a chiral reagent in the asymmetric synthesis of important compounds.

9.
Parasitology ; 149(4): 490-495, 2022 04.
Article in English | MEDLINE | ID: mdl-35109958

ABSTRACT

Cutaneous leishmaniasis (CL) is a spectrum of clinical manifestations characterized by severe skin ulcerations that leads to social stigma. There are limited treatment options for CL, and the available drugs are becoming less efficacious due to drug resistance. More efficacious and safer antileishmanial drugs are needed. In this study, the biological effect of seven synthetically accessible nitroaromatic compounds was evaluated in vitro against amastigotes of Leishmania amazonensis, followed by in vivo evaluation using mouse models of CL. Two compounds (6 and 7) were active against amastigotes in vitro [half-maximal effective concentration (EC50): 4.57 ± 0.08 and 9.19 ± 0.68 µm, respectively], with selectivity indexes >50, and the other compounds were not selective. In vivo, compounds 6 and 7 (10 mg kg−1, twice a day for 14 days) failed to reduce skin lesion sizes and parasite loads determined by light microscopy of lesion imprints and quantitative polymerase chain reaction. Nevertheless, the in vitro leishmanicidal efficacy sustained their use as templates for nitroimidazole-based antileishmanial drug discovery programmes focusing on analogues with more suitable properties.


Subject(s)
Antiprotozoal Agents , Leishmania mexicana , Leishmaniasis, Cutaneous , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Leishmaniasis, Cutaneous/drug therapy , Mice , Mice, Inbred BALB C , Nitro Compounds/therapeutic use
10.
Molecules ; 26(4)2021 Feb 14.
Article in English | MEDLINE | ID: mdl-33673007

ABSTRACT

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2-4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC50 in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.


Subject(s)
Antimalarials/pharmacology , Bridged Bicyclo Compounds/pharmacology , Plasmodium/drug effects , Quinolines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Hep G2 Cells , Humans , Quinolines/chemical synthesis , Quinolines/chemistry
11.
ACS Med Chem Lett ; 11(11): 2139-2145, 2020 Nov 12.
Article in English | MEDLINE | ID: mdl-33214821

ABSTRACT

Emerging infectious diseases like those caused by arboviruses such as Venezuelan equine encephalitis virus (VEEV) pose a serious threat to public health systems. Development of medical countermeasures against emerging infectious diseases are of utmost importance. In this work, an acrylate and vinyl sulfone-based chemical series was investigated as promising starting scaffolds against VEEV and as inhibitors of the cysteine protease domain of VEEV's nonstructural protein 2 (nsP2). Primary screen and dose response studies were performed to evaluate the potency and cytotoxicity of the compounds. The results provide structural insights into a new class of potent nonpeptidic covalent inhibitors of nsP2 cysteine protease represented by compound 11 (VEEV TrD, EC50 = 2.4 µM (HeLa), 1.6 µM (Vero E6)). These results may facilitate the evolution of the compounds into selective and broad-spectrum anti-alphaviral drug leads.

12.
Antimicrob Agents Chemother ; 64(12)2020 11 17.
Article in English | MEDLINE | ID: mdl-32928731

ABSTRACT

Phenotypic assay against Leishmania amazonensisin vitro and in vivo led to identification of an adamantyl-based phenyl sulfonyl acetamide (compound 1) as a promising antileishmanial agent. Compound 1 inhibited the growth of intracellular forms of L. amazonensis (50% inhibitory concentration [IC50] = 4 µM) and exhibited low toxicity to host cells, with a selectivity index (SI) of >125. However, in a cutaneous leishmaniasis (CL) mouse model, compound 1 did not reduce lesions and parasite load when administered as monotherapy or when given simultaneously with a suboptimal dose of miltefosine.


Subject(s)
Antiprotozoal Agents , Leishmania mexicana , Leishmania , Leishmaniasis, Cutaneous , Acetamides , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Leishmaniasis, Cutaneous/drug therapy , Mice , Mice, Inbred BALB C
13.
Bioorg Med Chem Lett ; 30(14): 127217, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32527539

ABSTRACT

The number of reported cases of Human African Trypanosmiasis (HAT), caused by kinetoplastid protozoan parasite Trypanosoma brucei, is declining in sub-Saharan Africa. Historically, such declines are generally followed by periods of higher incidence, and one of the lingering public health challenges of HAT is that its drug development pipeline is historically sparse. As a continuation of our work on new antitrypanosomal agents, we found that partially saturated quinoline-based vinyl sulfone compounds selectively inhibit the growth of T. brucei but displayed relatively weak inhibitory activity towards T. brucei's cysteine protease rhodesain. While two nitroaromatic analogues of the quinoline-based vinyl sulfone compounds displayed potent inhibition of T. brucei and rhodesain. The quinoline derivatives and the nitroaromatic-based compounds discovered in this work can serve as leads for ADME-based optimization and pre-clinical investigations.


Subject(s)
Antiprotozoal Agents/pharmacology , Cysteine Proteases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Sulfones/pharmacology , Trypanosoma brucei brucei/drug effects , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Trypanosoma brucei brucei/growth & development , Trypanosoma brucei brucei/metabolism
14.
Chemistry ; 26(25): 5639-5647, 2020 May 04.
Article in English | MEDLINE | ID: mdl-31953882

ABSTRACT

MicroRNAs (miRNAs) modulate the expression of over 30 % of mammalian genes during development and apoptosis, and abnormal expression of miRNAs may lead to a range of human pathologies. Therefore, analysis of miRNAs is valuable for disease diagnostics. In this work, a novel one-pot fluorescence derivatization strategy was developed for miRNA analysis. The mechanism of the derivatization reaction was explored by using instrumental methods, including liquid chromatography, fluorescence spectroscopy, and mass spectrometry. Highly fluorescent N6 -ethenoadenine (ϵ-adenine) was formed and detached from the miRNA sequence through the reaction of adenine in nucleic acids with 2-chloroacetaldehyde (CAA) at 100 °C. This is the first experimental evidence that the cooperation of formed ϵ-adenine and water-mediated hydrogen-bond interaction between the proton at the 2'- and the oxyanion at 3'-positions stabilized the oxocarbenium significantly, which makes the depurination and derivatization of miRNA highly effective. Based on this derivatization strategy, a facile and sensitive high-performance liquid chromatography method was developed for quantitative assay of miRNAs. In combination with magnetic solid-phase extraction (MSPE), the HPLC method was shown to be useful for the determination of microRNAs at sub-picomolar level in serum samples.


Subject(s)
Acetaldehyde/analogs & derivatives , Adenine/chemistry , MicroRNAs/analysis , Spectrometry, Fluorescence/methods , Acetaldehyde/chemistry , Chromatography, High Pressure Liquid/methods , Fluorescence , Humans , Mass Spectrometry , Water
15.
Bioorg Med Chem Lett ; 28(9): 1647-1651, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29609908

ABSTRACT

A series of natural products-based phenyl sulfone derivative and their property-based analogues were investigated as potential growth inhibitors of Trypanosoma brucei. Trypanosoma brucei is a kinetoplastid protozoan parasite that causes trypanosomiasis. In this work, we found that nopol- and quinoline-based phenyl sulfone derivative were the most active and selective for T. brucei, and they were not reactive towards the active thiol of T. brucei's cysteine protease rhodesain. A thiol reactive variant of the quinoline-based phenyl sulfone was subsequently investigated and found to be a moderate inhibitor of rhodesain. The quinoline-based compound that is not reactive towards rhodesain can serve a template for phenotypic-based lead discovery while its thiol-active congener can serve as template for structure-based investigation of new antitrypanosomal agents.


Subject(s)
Biological Products/pharmacology , Drug Discovery , Quinolines/pharmacology , Sulfones/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Biological Products/chemical synthesis , Biological Products/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Quinolines/chemistry , Structure-Activity Relationship , Sulfones/chemistry , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry
16.
Molecules ; 23(2)2018 Feb 08.
Article in English | MEDLINE | ID: mdl-29419735

ABSTRACT

The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory activity against Trypanosoma brucei. The active principle in the fraction was isolated, purified, and characterized by NMR and mass spectrometry. The antitrypanosomal agent in the CHCl3 extract of T. longipes leaves is the pentacyclic triterpenoid bauerenol acetate. A metabolite profiling assay suggest that the triterpenoid influences cholesterol metabolism. The molecular target(s) of bauerenol and its acetate, like many other antiparasitic pentacyclic triterpenoids is/are unknown, but they present privileged structural scaffolds that can be explored for structure-based activity optimization studies using phenotypic assays.


Subject(s)
Plant Extracts/chemistry , Plant Extracts/pharmacology , Tabernaemontana/chemistry , Triterpenes/chemistry , Triterpenes/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Parasitic Sensitivity Tests , Trypanosoma brucei brucei/drug effects
17.
Sci Pharm ; 85(1)2017 Jan 27.
Article in English | MEDLINE | ID: mdl-28134827

ABSTRACT

Trichomoniasis, caused by the parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually-transmitted disease, and there can be severe complications from trichomoniasis. Antibiotic resistance in T. vaginalis is increasing, but there are currently no alternatives treatment options. There is a need to discover and develop new chemotherapeutic alternatives. Plant-derived natural products have long served as sources for new medicinal agents, as well as new leads for drug discovery and development. In this work, we have carried out an in silico screening of 952 antiprotozoal phytochemicals with specific protein drug targets of T. vaginalis. A total of 42 compounds showed remarkable docking properties to T. vaginalis methionine gamma-lyase (TvMGL) and to T. vaginalis purine nucleoside phosphorylase (TvPNP). The most promising ligands were polyphenolic compounds, and several of these showed docking properties superior to either co-crystallized ligands or synthetic enzyme inhibitors.

18.
Molecules ; 21(10)2016 Oct 19.
Article in English | MEDLINE | ID: mdl-27775577

ABSTRACT

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.


Subject(s)
Antiprotozoal Agents/pharmacology , Biological Products/pharmacology , Neglected Diseases/drug therapy , Protozoan Infections/drug therapy , Protozoan Proteins/chemistry , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/therapeutic use , Biological Products/chemistry , Biological Products/therapeutic use , Computer Simulation , Drug Discovery , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Phytotherapy , Protozoan Proteins/metabolism , Structure-Activity Relationship
19.
J Mol Graph Model ; 69: 78-91, 2016 09.
Article in English | MEDLINE | ID: mdl-27588363

ABSTRACT

Zika virus (ZIKV) is an arbovirus that has infected hundreds of thousands of people and is a rapidly expanding epidemic across Central and South America. ZIKV infection has caused serious, albeit rare, complications including Guillain-Barré syndrome and congenital microcephaly. There are currently no vaccines or antiviral agents to treat or prevent ZIKV infection, but there are several ZIKV non-structural proteins that may serve as promising antiviral drug targets. In this work, we have carried out an in-silico search for potential anti-Zika viral agents from natural sources. We have generated ZIKV protease, methyltransferase, and RNA-dependent RNA polymerase using homology modeling techniques and we have carried out molecular docking analyses of our in-house virtual library of phytochemicals with these protein targets as well as with ZIKV helicase. Overall, 2263 plant-derived secondary metabolites have been docked. Of these, 43 compounds that have drug-like properties have exhibited remarkable docking profiles to one or more of the ZIKV protein targets, and several of these are found in relatively common herbal medicines, suggesting promise for natural and inexpensive antiviral therapy for this emerging tropical disease.


Subject(s)
Computer Simulation , Drug Evaluation, Preclinical , Phytochemicals/analysis , Phytochemicals/pharmacology , Zika Virus/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Ligands , Molecular Docking Simulation , Phytochemicals/chemistry , Protein Structure, Secondary , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/metabolism , Structural Homology, Protein , Viral Nonstructural Proteins/chemistry
20.
Comput Biol Chem ; 64: 163-184, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27387412

ABSTRACT

Alphaviruses such as Chikungunya virus (CHIKV), O'Nyong-Nyong virus (ONNV), Ross River virus (RRV), Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that can cause fevers, rash, and rheumatic diseases (CHIKV, ONNV, RRV) or potentially fatal encephalitis (EEEV, VEEV, WEEV) in humans. These diseases are considered neglected tropical diseases for which there are no current antiviral therapies or vaccines available. The alphavirus non-structural protein 2 (nsP2) contains a papain-like protease, which is considered to be a promising target for antiviral drug discovery. In this work, molecular docking analyses have been carried out on a library of 2174 plant-derived natural products (290 alkaloids, 664 terpenoids, 1060 polyphenolics, and 160 miscellaneous phytochemicals) with the nsP2 proteases of CHIKV, ONNV, RRV, EEEV, VEEV, WEEV, as well as Aura virus (AURV), Barmah Forest Virus (BFV), Semliki Forest virus (SFV), and Sindbis virus (SINV) in order to identity structural scaffolds for inhibitor design or discovery. Of the 2174 phytochemicals examined, a total of 127 showed promising docking affinities and poses to one or more of the nsP2 proteases, and this knowledge can be used to guide experimental investigation of potential inhibitors.


Subject(s)
Alphavirus/chemistry , Protease Inhibitors/isolation & purification , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Molecular Docking Simulation , Protease Inhibitors/chemistry
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