Systematic Analysis of Clemastine, a Candidate Apicomplexan Parasite-Selective Tubulin-Targeting Agent

Abbaali, Izra; Truong, Danny A.; Day, Shania D.; Haro-Ramirez, Nancy; Morrissette, Naomi S.

doi:10.3390/ijms23010068

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…Moreover, it has also shown antiprotozan activity against the parasites of the apicomplexa group, Toxoplasma gondii and Plasmodium spp. ( Abbaali et al, 2021 ). The mechanism of action of clemastine in protozoa relies on its bind and destabilization of the TRiC/CCT chaperonin ( Abbaali et al, 2021 ; Lu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…( Abbaali et al, 2021 ). The mechanism of action of clemastine in protozoa relies on its bind and destabilization of the TRiC/CCT chaperonin ( Abbaali et al, 2021 ; Lu et al, 2020 ). This heterooligomeric complex is required for the folding of the cytoskeletal proteins actin and tubulin, which are part of the microfilaments and microtubules of the cells, as well as been involved in the cell division ( Grantham, 2020 ; Wang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…These compounds encompass a range of bioactivities, each demonstrating activity or suspected activity against SARS-CoV-2, the virus responsible for the ongoing pandemic. Notably, these compounds have displayed promising biological activities not only in the fight against SARS-CoV-2 but also against other infectious agents, including parasitic protozoa ( Abbaali et al, 2021 ; Almeida-Paes et al, 2021 ; El Saftawy et al, 2024 ; Reigada et al, 2019 ). As the demand for innovative treatments against the deadly N. fowleri pathogen intensifies, exploring the potential of COVID Box compounds to address this amoebic infection emerges as a highly auspicious avenue for research.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box

Chao-Pellicer,

Arberas-Jiménez,

Sifaoui

et al. 2024

International Journal for Parasitology: Drugs and Drug Resistan

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box

Chao-Pellicer,

Arberas-Jiménez,

Sifaoui

et al. 2024

International Journal for Parasitology: Drugs and Drug Resistan

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“…Finally, it must be emphasized that several drugs used in glaucoma treatment [633][634][635] have antitoxoplasmic activity, including statins [296,642,[684][685][686][687], antihistaminic agents hydroxyzine, clemastine [650,688], ketotifen [689], adrenergics [676,677], sulfonamides (sulfadiazine, sulfamethoxazole, sulfadoxine) [678][679][680], antipsychiatric agents [646,690] (nb. this group of drugs showed direct correlation between clinical potency and presynaptic influence on dopamine neurons [691]), immunosuppressants, immunomodulators, anticancer drugs [680].…”

Section: Antidepressantmentioning

confidence: 99%

Solving the New Puzzle(s) 2014-2022: Flammer Syndrome Probably Represents a Mild Endophenotype of Raynaud’s Phenomenon Mainly Associated with Ocular Disturbances and Also Due to Latent T. gondii Infection

Prandota¹

2023

J Clin Med Cur Res

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negative effect on quality of life [9]. The study of 334 healthy subjects aged 50 years or elder in Japan showed that proportion of participants with increased sensitivity to cold widely ranged (6.1%-30.8% men, 14.3%-28.3% women) [12].In Eastern Asian populations CHHF occurs in 20%-52% of subjects [13][14][15], and ratio of men to women is 2:3 [16]. In Japan, this condition called "hiesho" is quite common involving over 60% of females, and in the latter stage of pregnancy "hiesho" manifests in about 40% of women, particularly in the advanced maternal age [17,18]. One study comparing Japanese with Brazilians reported that 57% of Brazilian pregnant women were aware of cold sensations [19,20]. CHHF is associated also with RP, gastric disturbances [21], as well as gynecological disorders, such as infertility and dysmenorrhea [22,23]. Nb. T. gondii infection causes ovarian dysfunction and disturbances in sperm motility, viability and concentration values, epididymis weight, and testicle inflammation [24][25][26][27][28].The presence of "hiesho" was found to be risk factor which can also lead to abnormal delivery because of weak labor pains, prolonged labor and atonic bleeding, premature delivery, amnion membrane rupture [17,29,30].In this context, it should be added that traditional Japanese fish dishes sushi and sashimi may, at least in part, play a role in development of these disorders [31], especially that wide distribution of T. gondii amongst sea fish and mammals may affect human health worldwide (e.g. the highest prevalence of the pathogen was found in otter (54.8%), and dolphin, whale and porpoise (30.92%) [32]. B. FS heritability.In Europe, most of FS symptoms appear in puberty and alleviate along with age, in women after menopause begun [33], albeit in the study of 3067 persons aged 65 years or elder 23.6% men and 28.6% women had cold extremities [34]. Importantly, parents of FS subjects also had similar symptoms which may suggest a heritability of this clinical entity [3,4]. Moreover, Konieczka & Erb [4] noted that there is a relationship between FS and RP, and suggested a genetic background of RP [35][36][37][38], but they believed that additional factor(s) may also play a role [4,35]. Nb. genetic factors appeared to be important in the development of RP as has been demonstrated in one familial and twin study [39]. FS often occurs in individuals who are slender, have a low blood pressure, are active, but also have unusually cold extremities, increased pain sensitivity, altered circadian rhythm, and prolonged falling asleep time [40,41]. C. Pathophysiological changes in FS.Individuals with FS have the autonomic nervous system imbalance with sympathetic predominance [4,42], lymphocytes and leukocytes in the eye have altered gene expression, and activated astrocytes in the retina also change their gene expression and morphology [2,[43][44][45], slightly increased plasma endothelin-1 (ET-1) levels, and increased systemic oxidative stress [5,46]. They also have enhanced sensitivity to some drugs, such as for ...

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Toxoplasma replication is inhibited by MMV676477 without development of resistance

Abbaali,

Truong,

Wetzel

et al. 2024

Cytoskeleton

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Protozoan parasites cause life‐threatening infections in both humans and animals, including agriculturally significant livestock. Available treatments are typically narrow spectrum and are complicated by drug toxicity and the development of resistant parasites. Protozoan tubulin is an attractive target for the development of broad‐spectrum antimitotic agents. The Medicines for Malaria Pathogen Box compound MMV676477 was previously shown to inhibit replication of kinetoplastid parasites, such as Leishmania amazonensis and Trypanosoma brucei, and the apicomplexan parasite Plasmodium falciparum by selectively stabilizing protozoan microtubules. In this report, we show that MMV676477 inhibits intracellular growth of the human apicomplexan pathogen Toxoplasma gondii with an EC50 value of ~50 nM. MMV676477 does not stabilize vertebrate microtubules or cause other toxic effects in human fibroblasts. The availability of tools for genetic studies makes Toxoplasma a useful model for studies of the cytoskeleton. We conducted a forward genetics screen for MMV676477 resistance, anticipating that missense mutations would delineate the binding site on protozoan tubulin. Unfortunately, we were unable to use genetics to dissect target interactions because no resistant parasites emerged. This outcome suggests that future drugs based on the MMV676477 scaffold would be less likely to be undermined by the emergence of drug resistance.

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Systematic Analysis of Clemastine, a Candidate Apicomplexan Parasite-Selective Tubulin-Targeting Agent

Cited by 5 publications

References 47 publications

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box

Solving the New Puzzle(s) 2014-2022: Flammer Syndrome Probably Represents a Mild Endophenotype of Raynaud’s Phenomenon Mainly Associated with Ocular Disturbances and Also Due to Latent T. gondii Infection

Toxoplasma replication is inhibited by MMV676477 without development of resistance

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