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- Title
Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics.
- Authors
Lautens, Margot J.; Tan, June H.; Serrat, Xènia; Del Borrello, Samantha; Schertzberg, Michael R.; Fraser, Andrew G.
- Abstract
Soil transmitted helminths (STHs) are major human pathogens that infect over a billion people. Resistance to current anthelmintics is rising and new drugs are needed. Here we combine multiple approaches to find druggable targets in the anaerobic metabolic pathways STHs need to survive in their mammalian host. These require rhodoquinone (RQ), an electron carrier used by STHs and not their hosts. We identified 25 genes predicted to act in RQ-dependent metabolism including sensing hypoxia and RQ synthesis and found 9 are required. Since all 9 have mammalian orthologues, we used comparative genomics and structural modeling to identify those with active sites that differ between host and parasite. Together, we found 4 genes that are required for RQ-dependent metabolism and have different active sites. Finding these high confidence targets can open up in silico screens to identify species selective inhibitors of these enzymes as new anthelmintics. Author summary: Soil-transmitted parasitic worms infect over a billion humans worldwide. In recent years, there has been increasing resistance to existing drugs that are used to treat parasitic infections and this has accelerated the need to develop new classes of drugs. Parasitic worms survive in the low oxygen environment of the host gut, using a special electron carrier, rhodoquinone. Since rhodoquinone is not used or made in humans, enzymes that use or make rhodoquinone are good targets for the development of new drugs. Here, we first identify genes that are important for parasites to carry out these rhodoquinone-dependent processes. Since many of these genes are also present in the human genome and we only want to target the parasite version, we then looked for sequence differences in these genes between parasites and humans to identify parasite-specific binding pockets in the enzymes. These sequence differences may allow for drugs which bind only to the parasite-version of the enzymes. From this, we have identified 4 high-confidence targets that can be used to guide the design of new anti-parasitic drugs.
- Subjects
ANTHELMINTICS; HELMINTHS; COMPARATIVE genomics; ENZYMES; PARASITIC diseases; QUINONE; GENE targeting; DIOXYGENASES
- Publication
PLoS Neglected Tropical Diseases, 2021, Vol 15, Issue 11, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0009991