Advances in anti-Trichomonas vaginalis target and drug research

doi:10.12140/j.issn.1000-7423.2024.01.015

Abstract

Abstract:

Trichomonas vaginalis mainly invades the human genitourinary system and is a common non-viral sexually transmitted pathogen in clinics. Oral metronidazole is a widely used treatment, but the resistance of T. vaginalis to metronidazole has been spreading due to monotherapies in the past, so it is urgent to find alternative means. In this paper, the relavent research on anti-T. vaginalis targets and treatments in recent years were summarized and analyzed. The new advances were specifically introduced to provide a reference for future research and applications.

Key words: Trichomoniasis vaginalis, Target, Drug, Research progress

CLC Number:

R382.211

ZHUO Xin, HUANG Cuilan. Advances in anti-Trichomonas vaginalis target and drug research[J]. CHINESE JOURNAL OF PARASITOLOGY AND PARASITIC DISEASES, 2024, 42(1): 105-110.

Figures/Tables 1

靶标	候选药物	作用特点	文献
20S蛋白酶体	CP-17	低浓度优先抑制β5，高浓度同时抑制β5、β2。体外活性较甲硝唑强，细胞毒性较CPB低	[8-9]
磷酸丙糖异构酶	A4	与阴道毛滴虫磷酸丙糖异构酶结合，但不抑制其酶活性。有体外杀滴虫活性，无细胞毒性	[11]
碳酸酐酶	乙酰唑胺依索唑胺	取代水分子/氢氧根离子与锌离子结合，抑制碳酸酐酶活性，二者的抑制常数达到纳摩尔级	[16]
金属肽酶TvMP50	铜-苯二酮	与TvMP50活性中心的组氨酸335相互作用，减少金属肽酶相关基因的表达；IC₅₀达0.84 µmol/L	[18,34]
G6PD-6PGL	CNZ-3、 CNZ-17	CNZ-3竞争性抑制，CNZ-177非竞争性抑制；IC₅₀值分别为93.0 、356.0 μmol/L；CNZ-3不具备选择性，CNZ-17选择性较强	[19]
黏附相关蛋白	-	黏附蛋白33、黏附蛋白65与人促凋亡蛋白BNIP3相互作用；肌动蛋白加帽蛋白亚基调控滴虫的细胞骨架，细胞骨架抑制剂和酪蛋白激酶-2抑制剂可抑制这种调节作用	[20-21] [23]
-	PH100	降低肽酶活性，诱导滋养体凋亡；IC₅₀达14.8 µmol/L，MIC可达80 µmol/L，与甲硝唑有协同作用，细胞毒性低，无溶血作用	[24]
金属肽酶TvMP50	ATZ-1 ATZ-2	ATZ-1、ATZ-2与TvMP50活性中心强相互作用，显著下调TvMP50的活性，同时降低TvMP50的基因表达。以剂量依赖性方式抑制阴道毛滴虫的生长，IC₅₀分别为0.15 、0.18 μg/ml	[27]
嘌呤核苷磷酸化酶、乳酸脱氢酶等	QDA-1	促进活性氧产生和脂质过氧化，IC₅₀为113.8 μmol/L，160 μmol/L时完全抑制滋养体生长，有一定的细胞毒性	[28]
金属肽酶	PH152	作用于金属肽酶的铁离子，IC₅₀为16.88 μmol/L，对人细胞无毒性	[29]
丙酮酸铁氧还蛋白氧化还原酶	Amixicile	对9个分离株的MIC一致性较低，中位MIC值为6.25 μmol/L（1.56 μmol/L，12.5 μmol/L）	[30]
G6PD-6PGL	O₂N-BZM7、 O₂N-BZM9	二者均能改变G6PD-6PGL的三维结构，导致酶的活性丧失，且O₂N-BZM9比O₂N-BZM7更快形成酶-抑制剂复合物。IC₅₀分别为22 、240 μmol/L	[31]
嘌呤核苷磷酸化酶	4-羟基查尔酮	作用于嘌呤核苷磷酸化酶的氨基酸残基，4-羟基查尔酮的IC₅₀为27.5 μmol/L，对人红细胞无毒性	[37]
-	SQ109	SQ109能导致滋养体出现表面凸起增加，胞质内氢化小体肿胀等超微结构变化，IC₅₀为3.15 μmol/L	[39]

References 42

[1]	van Gerwen OT, Camino AF, Sharma J, et al. Epidemiology, natural history, diagnosis, and treatment of Trichomonas vaginalis in men[J]. Clin Infect Dis, 2021, 73(6): 1119-1124. doi: 10.1093/cid/ciab514
[2]	Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016[J]. Bull World Health Organ, 2019, 97(8): 548-562P. doi: 10.2471/BLT.18.228486
[3]	Hamar B, Teutsch B, Hoffmann E, et al. Trichomonas vaginalis infection is associated with increased risk of cervical carcinogenesis: a systematic review and meta-analysis of 470 000 patients[J]. Int J Gynaecol Obstet, 2023, 163(1): 31-43. doi: 10.1002/ijgo.v163.1
[4]	Duan YJ, Li PJ, Sang YH, et al. Affect of Trichomonas vaginalis infection on male reproductive system and its mechanisms[J]. Chin J Parasitol Parasit Dis, 2021, 39(4): 532-536. (in Chinese)
	(段玉娟, 李朋举, 桑雨慧, 等. 阴道毛滴虫感染对男性生殖系统的影响及其机制[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(4): 532-536.) doi: 10.12140/j.issn.1000-7423.2021.04.018
[5]	Zhang ZC, Li DX, Li YH, et al. The correlation between Trichomonas vaginalis infection and reproductive system cancer: a systematic review and meta-analysis[J]. Infect Agent Cancer, 2023, 18(1): 15. doi: 10.1186/s13027-023-00490-2
[6]	Cooperative Group of Infectious Disease, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. Diagnosis and treatment guidelines for trichomoniasis (2021 revised edition)[J]. Chin J Obstet Gynecol, 2021, 56(1): 7-10. (in Chinese)
	(中华医学会妇产科学分会感染性疾病协作组. 阴道毛滴虫感染诊治指南(2021修订版)[J]. 中华妇产科杂志, 2021, 56(1): 7-10.)
[7]	Squires S, Mcfadzean JA. Strain sensitivity of Trichomonas vaginalis to metronidazole[J]. Br J Vener Dis, 1962, 38(4): 218-219.
[8]	Mtshali A, Ngcapu S, Govender K, et al. In vitro effect of 5-nitroimidazole drugs against Trichomonas vaginalis clinical isolates[J]. Microbiol Spectr, 2022, 10(4): e0091222.
[9]	O’Donoghue AJ, Bibo-Verdugo B, Miyamoto Y, et al. 20S proteasome as a drug target in Trichomonas vaginalis[J]. Antimicrob Agents Chemother, 2019, 63(11): e00448-e00419.
[10]	Fajtova P, Hurysz BM, Miyamoto Y, et al. Development of subunit selective substrates for Trichomonas vaginalis proteasome[J]. BioRxiv, 2023: 2023.04.05.535794.
[11]	Silhan J, Fajtova P, Bartosova J, et al. Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors[J]. bioRxiv, 2023: 2023.08.17.553660.
[12]	Benítez-Cardoza CG, Brieba LG, Arroyo R, et al. Triosephosphate isomerase as a therapeutic target against trichomoniasis[J]. Mol Biochem Parasitol, 2021, 246: 111413. doi: 10.1016/j.molbiopara.2021.111413
[13]	Vique-Sánchez JL, Caro-Gómez LA, Brieba LG, et al. Developing a new drug against trichomoniasis, new inhibitory compounds of the protein triosephosphate isomerase[J]. Parasitol Int, 2020, 76: 102086. doi: 10.1016/j.parint.2020.102086
[14]	Urbański LJ, di Fiore A, Azizi L, et al. Biochemical and structural characterisation of a protozoan beta-carbonic anhydrase from Trichomonas vaginalis[J]. J Enzyme Inhib Med Chem, 2020, 35(1): 1292-1299. doi: 10.1080/14756366.2020.1774572
[15]	Urbański LJ, Angeli A, Mykuliak VV, et al. Biochemical and structural characterization of beta-carbonic anhydrase from the parasite Trichomonas vaginalis[J]. J Mol Med, 2022, 100(1): 115-124. doi: 10.1007/s00109-021-02148-1
[16]	Urbański LJ, Angeli A, Hytönen VP, et al. Inhibition of the newly discovered β-carbonic anhydrase from the protozoan pathogen Trichomonas vaginalis with inorganic anions and small molecules[J]. J Inorg Biochem, 2020, 213: 111274. doi: 10.1016/j.jinorgbio.2020.111274
[17]	Urbański LJ, Angeli A, Hytönen VP, et al. Inhibition of the β-carbonic anhydrase from the protozoan pathogen Trichomonas vaginalis with sulphonamides[J]. J Enzyme Inhib Med Chem, 2021, 36(1): 329-334.
[18]	Vargas Rigo G, Gomes Cardoso F, Bongiorni Galego G, et al. Metallopeptidases as key virulence attributes of clinically relevant Protozoa: new discoveries, perspectives, and frontiers of knowledge[J]. Curr Protein Pept Sci, 2023, 24(4): 307-328. doi: 10.2174/1389203724666230306153001
[19]	Rigo GV, Cardoso FG, Pereira MM, et al. Peptidases are potential targets of copper(II)-1, 10-phenanthroline-5, 6-dione complex, a promising and potent new drug against Trichomonas vaginalis[J]. Pathogens, 2023, 12(5): 745. doi: 10.3390/pathogens12050745
[20]	Martínez-Rosas V, Hernández-Ochoa B, Navarrete-Vázquez G, et al. Kinetic and molecular docking studies to determine the effect of inhibitors on the activity and structure of fused G6PD-6PGL protein from Trichomonas vaginalis[J]. Molecules, 2022, 27(4): 1174. doi: 10.3390/molecules27041174
[21]	Zhang ZC, Song XX, Deng YY, et al. Trichomonas vaginalis adhesion protein 65 (TvAP65) modulates parasite pathogenicity by interacting with host cell proteins[J]. Acta Trop, 2023, 246: 106996. doi: 10.1016/j.actatropica.2023.106996
[22]	Zhang ZC, Deng YY, Sheng WX, et al. The interaction between adhesion protein 33 (TvAP33) and BNIP3 mediates the adhesion and pathogenicity of Trichomonas vaginalis to host cells[J]. Parasit Vectors, 2023, 16(1): 210. doi: 10.1186/s13071-023-05798-x
[23]	Gaglianone M, Laugieri ME, Rojas AL, et al. The L-rhamnose biosynthetic pathway in Trichomonas vaginalis: identification and characterization of UDP-D-glucose 4, 6-dehydratase[J]. Int J Mol Sci, 2022, 23(23): 14587. doi: 10.3390/ijms232314587
[24]	Wang KH, Chang JY, Li FA, et al. An atypical F-actin capping protein modulates cytoskeleton behaviors crucial for Trichomonas vaginalis colonization[J]. Microbiol Spectr, 2023, 11(4): e0059623.
[25]	Weber JI, Rigo GV, Rocha DA, et al. Modulation of peptidases by 2, 4-diamine-quinazoline derivative induces cell death in the amitochondriate parasite Trichomonas vaginalis[J]. Biomed Pharma, 2021, 139: 111611.
[26]	Rodríguez-Villar K, Yépez-Mulia L, Cortés-Gines M, et al. Synthesis, antiprotozoal activity, and cheminformatic analysis of 2-phenyl-2H-indazole derivatives[J]. Molecules, 2021, 26(8): 2145. doi: 10.3390/molecules26082145
[27]	Ibáñez-Escribano A, Reviriego F, Vela N, et al. Promising hit compounds against resistant trichomoniasis: synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles[J]. Bioorg Med Chem Lett, 2021, 37: 127843. doi: 10.1016/j.bmcl.2021.127843
[28]	Mena-Rejón G, Pérez-Navarro Y, Torres-Romero JC, et al. Antitrichomonal activity and docking analysis of thiazole derivatives as TvMP50 protease inhibitors[J]. Parasitol Res, 2021, 120(1): 233-241. doi: 10.1007/s00436-020-06931-w pmid: 33073325
[29]	Alves MSD, Sena-Lopes Â, das Neves RN, et al. In vitro and in silico trichomonacidal activity of 2, 8-bis (trifluoromethyl) quinoline analogs against Trichomonas vaginalis[J]. Parasitol Res, 2022, 121(9): 2697-2711. doi: 10.1007/s00436-022-07598-1
[30]	Rigo GV, Joaquim AR, Macedo AJ, et al. Iron chelation and inhibition of metallopeptidases mediate anti-Trichomonas vaginalis activity by a novel 8-hydroxyquinoline derivative[J]. Bioorg Chem, 2022, 125: 105912. doi: 10.1016/j.bioorg.2022.105912
[31]	Jain E, Zaenker EI, Hoffman PS, et al. In vitro activity of amixicile against T. vaginalis from clinical isolates[J]. Parasitol Res, 2022, 121(8): 2453-2455. doi: 10.1007/s00436-022-07567-8
[32]	Hernández-Ochoa B, Martínez-Rosas V, Morales-Luna L, et al. Pyridyl methylsulfinyl benzimidazole derivatives as promising agents against Giardia lamblia and Trichomonas vaginalis[J]. Molecules, 2022, 27(24): 8902. doi: 10.3390/molecules27248902
[33]	Natto MJ, Hulpia F, Kalkman ER, et al. Deazapurine nucleoside analogues for the treatment of Trichomonas vaginalis[J]. ACS Infect Dis, 2021, 7(6): 1752-1764. doi: 10.1021/acsinfecdis.1c00075
[34]	Beteck RM, Isaacs M, Legoabe LJ, et al. Synthesis and in vitro antiprotozoal evaluation of novel metronidazole-Schiff base hybrids[J]. Arch Pharm, 2023, 356(3): e2200409.
[35]	Vargas Rigo G, Willig JB, Devereux M, et al. Oxidative damage by 1, 10-phenanthroline-5, 6-dione and its silver and copper complexes lead to apoptotic-like death in Trichomonas vaginalis[J]. Res Microbiol, 2023, 174(4): 104015. doi: 10.1016/j.resmic.2022.104015
[36]	de Souza TG, Benaim G, de Souza W, et al. Effects of amiodarone, amioder, and dronedarone on Trichomonas vaginalis[J]. Parasitol Res, 2022, 121(6): 1761-1773. doi: 10.1007/s00436-022-07521-8
[37]	de Giacometi M, Mayer JCP, de Mello AB, et al. Activity of compounds derived from benzofuroxan in Trichomonas vaginalis[J]. Exp Parasitol, 2023, 253: 108601. doi: 10.1016/j.exppara.2023.108601
[38]	Oliveira LR, Trein MR, Assis LR, et al. Phenolic chalcones as agents against Trichomonas vaginalis[J]. Bioorg Chem, 2023, 141: 106888. doi: 10.1016/j.bioorg.2023.106888
[39]	Herrera-España AD, Aguiar-Pech JA, Alvarez-Sánchez ME, et al. Lupeol acetate isolated from Chrysophyllum cainito L. fruit as a template for the synthesis of N-alkyl-arylsulfonamide derivatives and their synergistic effects with metronidazole against Trichomonas vaginalis[J]. Nat Prod Res, 2022, 36(21): 5508-5516. doi: 10.1080/14786419.2021.2018429
[40]	de Souza TG, Granado R, Benaim G, et al. Effects of SQ109 on Trichomonas vaginalis[J]. Exp Parasitol, 2023, 250: 108549. doi: 10.1016/j.exppara.2023.108549
[41]	Miyamoto Y, Aggarwal S, Celaje JJA, et al. Gold (I) phosphine derivatives with improved selectivity as topically active drug leads to overcome 5-nitroheterocyclic drug resistance in Trichomonas vaginalis[J]. J Med Chem, 2021, 64(10): 6608-6620. doi: 10.1021/acs.jmedchem.0c01926 pmid: 33974434
[42]	Ibáñez-Escribano A, Fonseca-Berzal C, Martínez-Montiel M, et al. Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis[J]. J Enzyme Inhib Med Chem, 2022, 37(1): 781-791 doi: 10.1080/14756366.2022.2041629