Trustworthiness of AI based predictions Aachen 2024
Jounal clab 2
1. Abstract:
Schistosomiasis is a water-born parasitic disease in humans caused by various species of
trematods of the genus Schistosoma. The effect of the infection causes impaired growth and
cognitive development in children; and in adults, hyper tension of abdominal blood pressure,
hepatospleenomegali, bladder cancer and kidney failure as a result of chronic infection. It is the
second most devastating parasitic disease in tropical and sub-tropical areas after malaria. More
than 200 million people worldwide have been infecting by the parasite. It is considered as a
neglected tropical disease (Hotez, 2007). Poor socioeconomic conditions are mainly responsible
for the transmission of the disease, the rate of which is increasing worldwide.
Transmission of the disease mainly occurs by cercariae which is a larvae form of parasite
Schistosoma. The parasite performs a complex life cycle where snail is intermediate host and
human is main host. The intermediate host- snail, releases the cercariae into fresh-water. Human
skin in contact with the contaminated fresh water results in penetration of the cercariae through
skin and transforms into larva which then migrates to the hepatic portal system as a part of its life
cycle. Control of the disease transmission mainly depends on the improvement in sanitation,
health education, snail control as well as chemotherapy. As there are no vaccines for the parasitic
disease reported untill now, chemotherapy is the best way to control the disease. The currently
available chemotherapeutic drugs for schistosomiasis are praziquantel (PZQ), Artemether, 2-
(alkylamino)-1-phenyl-1-ethanethiosulfuric acids, all of which are now limited in application.
PZQ is the most effective drug to the present time against all types of schistosomiasis and
considerably less side effects. As the drug target voltage-gated Ca2+ channels of pathogen, it is
able to induce contraction and therby paralyses but only in adult pathogens and it is believed I
has no effect on immature schistosomes. The efficacy of PZQ not only depends on the different
developmental stage of infection, but also on host’s immune system. As the paralyzed
schistosome is destroyed by phagosistosis of the immune system, the efficacy of PZQ needs
strong host immune system. Even though PZQ is effective for almost all types of
schistosomiasis, the drug alone has partial-protective activity. However the activity of the drug
become reduces due to the generation of resistant pathogen (Fallon, P.G. 1994). In the case of
other available drugs, Oxamniquine is mainly effective to treat intestinal schistosomiasis in
Africa and South America, whereas Metrifonate has been using to treat urinary schistosomiasis
2. worldwide, artemisisnin is significantly less effective against adult schistosome parasites. Due to
lake of proper treatment and preventive therapy the rate of the disease occurrence is increasing
rapidly worldwide and will become a remarkable threat to human populations in the near future.
The eradication of the disease is completely impossible, as there are no vaccine for the parasitic
disease has reported untill now. Under the present circumstances, a safe, non-toxic but effective
drug should be urgently introduced to control the schistosomiasis in novel way by targeting
common biochemical mechanism. Thioredoxin glutathione reductase (TGR) is one of such
common pathway which present in all developmental stages as well as in all infectious pathogen.
By quantitative high-throughput screen (qHTS) of NIH Molecular Libraries, followed by
confirmatory and target deconvolution assay, four promising series were identified (1. oxadiazole
2-oxides, 2. phosphinic amides, 3. quinolinyl sulfonamides , 4. Phosphoramidite) as Thioredoxin
glutathione reductase (TGR) inhibitors. The aim of this study was to analyse the activity
phosphinic amides and oxadiazole 2-oxides against antioxidant pathway at all developmental
stages of parasite as well as all major species infecting humans, and S. mansoni–infected mice.
Among the ten selected compound, 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide showed
most active against in-vitro adult pathogen as well as multiple parasitic stages and egg-
associated pathologies by generating NO. The protective activity of the compound was also
observed against the three major species of schistosome pathogen infecting human. The
cytotoxic effect of the compound was lower as compared to the PZQ.
Discussion:
The level of activity of compound 9 was equal to or better than that of the currently used drug, PZQ, and surpasses
all landmarks for new lead compounds for schistosomiasis control. The low cytotoxicity and high bioactivity and
tolerance by mice of compound 9 support the potential of this compound as a highly effective lead compound for
human schistosomiasis.
in the series of oxadiazole 2-oxides, 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide is
identified as the most active compound which showed a significant activity against almost all
stages of the parasite life cycle. Therefore it might be a effective drug to treat both short-term
and long-term schistosomiasis. Thus, the compound might be potential new drug which able to
treat schistosomiasis more effectively at any point during the infection. Unlike PZQ, the
compound able to reduce the larval count in lung, it might be a promising prophylactic drug for
schistosomiasis treatment. PZQ is much less effective against juvenile liver parasites than against adult
parasites, producing only a 25–30% reduction in worm burdens. Although artemether affords B80% reduction if
juvenile parasites are targeted, it is less effective against adult schistosome parasites, resulting in o50% reduction in
worm burden 31. In addition, compound 9 was found to be active against adults…..
3. compound 9 was found to be active against adults of the other main schistosome species infecting humans, S.
japonicum and S. haematobium. Therefore, compound 9, or its derivatives, could be useful……
The almost completely dependence on PZQ for schistosomiasis treatment lead to the increase of
developing resistant strains worldwide resulting in out-of-control of the disease effect. A the
compound have different mode of action than PZQ to kill the pathogen, might be a potential drug
to treat PZQ-resistant strain. Apart from this, the compound might be a perfect choice for
combination therapy with PZQ or artemisnin to treat more effectively than alone.
Future scope:
The analysis is undoubtedly a prominence step forward, but the goal of new schistomatosis drug
development is far from the point of view. Rather, it envisages an initiative point to develop new
safe but potential drug to control the divesting effect of sichtomatosis worldwide. Although the
study conclude that the compound has a less cytotoxic effect with better tolerance by mouse in
comparison to currently used drug PZQ, further study needs to confirm the protective activity
against all developmental stage of the compound is more than the currently used drug, PZQ.
Next goal would be to measure the efficiency of the compound against all developmental stage
in a single in vivo experiment by using PZQ as a positive control.
The compound act as TGR inhibitor lead to impairment of redox mechanism in pathogen,
ultimately kill it. Like PZQ, the killed pathogen in host tissue may be target by the host’s
immune system to eliminate by phagosytosis. Thus the efficacy of the drug might also be
depending on the host immunity; consequently sex, race or others. However the effect of the
compound on the host’s cell-enzyme: Thioredoxin Reductase (TrxR), Glutaredoxin (Grx) and
Glutathione Reductase (GR) also needs to analyze. By using various derivatives of the
compound, the efficacy of the drug might possible to increase selectively. As the compound
generates toxic NO, the side effects also need to analyze more details before using as drug.
It is important to conduct pharmacokinetic analysis of the compound for biological half life ,
excretion or elimination rate constant for the compound before going to clinical trial.
Ref:
4. 1. Hotez, P.J. et al. Control of neglected tropical diseases. N. Engl. J. Med. 357, 1018–1027
(2007).
2. Fallon, P.G. & Doenhoff, M.J. Drug-resistant schistosomiasis: resistance to praziquantel
and oxamniquine induced in Schistosoma mansoni in mice is drug specific. Am. J. Trop.
Med. Hyg. 51, 83–88 (1994).
3. Herwaldt, B.L., Tao, L.F., van Pelt, W., Tsang, V.C. & Bruce, J.I. Persistence of
Schistosoma haematobium infection despite multiple courses of therapy with
praziquantel. Clin. Infect. Dis. 20, 309–315 (1995).
4. Murray-Smith, S.Q., Scott, B.J., Barton, D.P. & Weinstein, P. A case of refractory
schistosomiasis. Med. J. Aust. 165, 458 (1996).
5. Ismail, M. et al. Resistance to praziquantel: direct evidence from Schistosoma mansoni
isolated from Egyptian villagers. Am. J. Trop. Med. Hyg. 60, 932–935 (1999).
6. Simeonov, A. et al. Quantitative high-throughput screen identifies inhibitors of the
Schistosoma mansoni redox cascade. PLoS Negl. Trop. Dis 2, e127 (2008).
7.