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[PMC free article] [PubMed] [CrossRef] [Google Scholar] 27. to protecting each other from drug resistance, two molecules to be combined need to be compatible for coformulation, should have matching pharmacokinetic profiles, and must not DGKH have unfavorable polypharmacology (4,C6). Ideally, the two molecules would potentiate each other, thereby decreasing the period of treatment and the required doses. Thus, combinatorial chemotherapy not only can reduce the risk of drug resistance but also can enhance drug safety and drug efficacy, enabling the ambitious goal of a single-exposure radical remedy (7, 8). Here we propose to support the matchmaking of antimalarial candidates by learning from yeast reverse Salinomycin sodium salt genetics. is probably the best analyzed of all eukaryotes. Only about 20% of its protein-coding genes are essential for growth on rich Salinomycin sodium salt medium (9). High-throughput crossing experiments have shown that many viable gene deletion mutants possess Salinomycin sodium salt synthetic phenotypes, i.e., growth defects that become apparent only in the absence of another nonessential gene. The concept of genetic synthetic lethality can be adopted to combination chemotherapy (8, 10,C12). The principal idea is usually to extrapolate from synthetic lethal gene pairs in to orthologous pairs of genes in is usually more closely related to than to (13). Thus, a drug combination inferred from yeast synthetic genetic lethality might enhance the toxicity to humans rather than enhancing the antimalarial efficacy. To avoid such a scenario, we developed an algorithm to exclude gene pairs that are conserved in recognized in BioGRID, we found that only 1 1,505 pairs (9.3%) had direct orthologues in for both gene products (Fig. 1). From this set, we tested all of the proteins for the presence of an orthologue in the human proteome, again referring to the downloaded OrthoMCL database. This assessment included Salinomycin sodium salt direct pairwise orthology between the or protein and a protein or indirect orthology in which either the malaria protein or its yeast orthologue belonged to an OrthoMCL group that also contained a human protein (Fig. 1). All of the gene pairs for which both gene products tested positive for direct or indirect human orthology were eliminated. This process yielded 37 pairs composed of 55 unique proteins that fulfilled the conditions that (i) their direct orthologues in exhibit synthetic lethality and (ii) at least one of the two proteins has neither a direct nor an indirect orthologue in the human proteome. Therefore, we suggest these pairs as targets for combinatorial chemotherapy. The comparative genomics pipeline (Fig. 1) is built with self-developed Python scripts that are available for download at the GitHub repository (https://github.com/suvi-subra/SynthLeth). Open in a separate windows FIG 1 Graphic representation of the algorithm, with the numbers of gene pairs that exceeded the filters; the final 37 are shown in Table 1. Yellow, cation/H+ antiporter (PfCHA), which is usually sensitive to known inhibitors such as KB-R7943 (20). Hubs of inferred interactions were apurinic/apyrimidinic endonuclease 1 (PfAPN1) and the U5 small nuclear ribonucleoprotein (PfSNU114) of the spliceosome, both of which are involved in the processing of nucleic acids. Two proteins in the target set were of particular pharmacological interest, namely, Ca2+-ATPase 4 (PfATP4) and phosphatidylinositol 4-kinase (PfPI4K). Either protein is usually targeted by new antimalarial candidates (21,C27). PfATP4 is the target of cipargamin and paired with PfCHA (Table 1), suggesting screening for potential synergy between cipargamin and KB-R7943. PfPI4K, the target of imidazolopiperazines and MMV390048, paired with ubiquitin-conjugating enzyme E2 (Table 1). An inhibitor of Atg8-Atg3 interactions was identified from your MMV Malaria Box (28), and ubiquitin-protein ligase E3 was proposed as an antimalarial target (29). The inferred link between phosphatidylinositol 4-kinase and ubiquitination suggests screening for potential synergy between PfPI4K inhibitors and proteasome inhibitors (30,C32). TABLE 1 Pairs of proteins suggested as targets for combinatorial chemotherapy, based on synthetic Salinomycin sodium salt lethal genetic interactions in oxidase subunit 1PFF1105cChorismate synthasePF14_0511Glucose-6-phosphate dehydrogenasePFL2465cThymidylate kinasePF13_0176Apurinic/apyrimidinic endonucleaseMAL13P1.346DNA repair endonucleasePF13_0176Apurinic/apyrimidinic endonucleasePFB0160wERCC1 nucleotide excision repair proteinPF13_0176Apurinic/apyrimidinic endonucleasePFF0715cEndonuclease III homologuePF13_0176Apurinic/apyrimidinic endonucleasePFD0865cCdc2-related protein kinase 1PFF0165cConserved protein, unknown functionPFL1635wSentrin-specific protease 1PF10_0092MetallopeptidasePF13_0251DNA topoisomerase 3PF10_0092MetallopeptidasePFF0775wPyridoxal kinase-like proteinPFF1025cPyridoxine biosynthesis proteinPF11_0192Histone acetyltransferasePFF1180wAnaphase-promoting complex subunitPFL2440wDNA repair proteinMAL7P1.94Prefoldin subunit 3PF11_0087DNA repair proteinPF10_0041U5 small nuclear ribonucleoproteinPFB0445cATP-dependent RNA helicasePF10_0041U5 small nuclear ribonucleoproteinPFE0925cATP-dependent RNA helicasePF10_0041U5 small nuclear ribonucleoproteinPF10_0294Pre-mRNA-splicing factor ATP-dependent RNA helicasePF10_0041U5 small nuclear ribonucleoproteinPFC1060cU4/U6.U5 tri-small-nuclear-ribonucleoprotein-associated protein 1PF10_0041U5 small nuclear ribonucleoproteinPF13_0096U4/U6.U5 tri-small-nuclear-ribonucleoprotein-associated protein 2PF10_0041U5 small nuclear ribonucleoproteinPFC0365wPre-mRNA-processing factor 19PF10_0041U5 small nuclear ribonucleoproteinPFD0685cStructural maintenance of chromosomes protein 3PF10_0041U5 small nuclear ribonucleoproteinMAL13P1.214Phosphoethanolamine proteinPFB0920wDnaJ proteinPFL1140wVacuolar iron transporterPFL0725wThioredoxin peroxidase 2 Open in a separate windows aSERCA, sarcoendoplasmic reticulum.