Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue

Abstract

Background Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure–function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored. Methods We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database (https://vectorbase.org/vectorbase/app) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases—were generated using the I-TASSER and Phyre protein modeling servers. Results Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%. Conclusions Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.

Repurposing DrugBank compounds as potential Plasmodium falciparum class 1a aminoacyl tRNA synthetase multi-stage pan-inhibitors with a specific focus on mitomycin

“…Site 4 presented another site of interest as it corresponds to the preferential binding sites of the other six compounds and has an estimated Dscore/SiteScore value of 0.804/0.883. Site 4 is located among α16, α18, α19 and α20 helices of the DALR anticodon binding domain (DALR-domain) ( Kim et al, 2014 ) which mediates tRNA recognition and binding ( Chakraborti et al, 2021 ; Manickam et al, 2018 ; Jain et al, 2016 ). The druggability potentials of these sites were further supported by their physicochemical properties such as estimations of surface exposure for Sites 2 (0.643) and 4 (0.590) that depict their accessibility to ligand molecules (see Supplementary Table S10 ).…”

Assessment of genetic diversity patterns of different serotypes of dengue virus, prevalent in patients from Kerala, India: a strain specific mutation study and its relevance to pathogenesis

“…The ADE occurs when patients contract a heterotypic secondary dengue virus infection and make additional complication for effective treatment of patients [46]. The development of Directly Active Antivirals (DAA) are an important area where scientists are trying to make some anti-dengue drugs which can suppress the all kinds of genetically diverse genotypes and/or serotypes of dengue virus [47; 48]. However, tremendous efforts of the scientists to find out some antiviral therapy, there is no anti dengue drugs in the market presently.…”

Malaria therapeutics: are we close enough?

“…Several antimalarial drugs are used worldwide to treat and prevent malaria infection [ 15 ]. Antimalarials are divided into several classes based on quinoline (4 and 8 aminoquinolines), cinchona alkaloids, diaminopyrimidine, sulfonamides, tetracyclines, naphthoquinones, and sesquiterpenes [ 16 , 17 ]. Antimalarials are used as prophylaxis for malaria, and most kill parasites in the infected RBCs.…”