In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 17, No. 9 ( 2023-9-5), p. e0011205-
Abstract:
Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura . Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris , the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC 50 values of ≤ 50 μM against T . muris ex vivo , and selected nine for testing in vivo . However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T . muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug development against whipworms.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0011205
DOI:
10.1371/journal.pntd.0011205.g001
DOI:
10.1371/journal.pntd.0011205.g002
DOI:
10.1371/journal.pntd.0011205.g003
DOI:
10.1371/journal.pntd.0011205.g004
DOI:
10.1371/journal.pntd.0011205.t001
DOI:
10.1371/journal.pntd.0011205.t002
DOI:
10.1371/journal.pntd.0011205.s001
DOI:
10.1371/journal.pntd.0011205.s002
DOI:
10.1371/journal.pntd.0011205.s003
DOI:
10.1371/journal.pntd.0011205.s004
DOI:
10.1371/journal.pntd.0011205.s005
DOI:
10.1371/journal.pntd.0011205.s006
DOI:
10.1371/journal.pntd.0011205.s007
DOI:
10.1371/journal.pntd.0011205.s008
DOI:
10.1371/journal.pntd.0011205.s009
DOI:
10.1371/journal.pntd.0011205.s010
DOI:
10.1371/journal.pntd.0011205.s011
DOI:
10.1371/journal.pntd.0011205.s012
DOI:
10.1371/journal.pntd.0011205.r001
DOI:
10.1371/journal.pntd.0011205.r002
DOI:
10.1371/journal.pntd.0011205.r003
DOI:
10.1371/journal.pntd.0011205.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2429704-5
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