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|Title:||Designed Chemical Intervention with Thiols for Prophylactic Contraception|
|Authors:||Sharma, Monika;Kumar, Lokesh;Jain, Ashish;Verma, Vikas;Sharma, Vikas;Kushwaha, Bhavana;Lal, Nand;Kumar, Lalit;Rawat, Tara;Dwivedi, A K;Maikhuri, J P;Sharma, V L;Gupta, Gopal|
|Keywords:||Sulfhydryls;Hexokinase;Microbicidal spermicide;Trichomonas vaginalis;Contraceptive film|
|Description:||Unlike somatic cells, sperm have several-fold more available-thiols that are susceptible to redox-active agents. The present study explains the mechanism behind the instant sperm-immobilizing and trichomonacidal activities of pyrrolidinium pyrrolidine-1-carbodithioate (PPC), a novel thiol agent rationally created for prophylactic contraception by minor chemical modifications of some known thiol drugs. PPC, and its three derivatives (with potential active-site blocked by alkylation), were synthesized and evaluated against live human sperm and metronidazole-susceptible and resistant Trichomonas vaginalis, in vitro. Sperm hexokinase activity was evaluated by coupled enzyme assay. PPC irreversibly immobilized 100% human sperm in ,30 seconds and totally eliminated Trichomonas vaginalis more efficiently than nonoxynol-9 and metronidazole. It significantly inhibited (P,0.001) thiol-sensitive sperm hexokinase. However, the molecule completely lost all its biological activities once its thiol group was blocked by alkylation. PPC was subsequently formulated into a mucoadhesive vaginal film using GRaS excipients and evaluated for spermicidal and microbicidal activities (in vitro), and contraceptive efficacy in rabbits. PPC remained fully active in quick-dissolving, mucoadhesive vaginal-film formulation, and these PPC-films significantly reduced pregnancy and fertility rates in rabbits. The films released ,90% of PPC in simulated vaginal fluid (pH 4.2) at 37uC in 5 minutes, in vitro. We have thus discovered a common target (reactive thiols) on chieflyanaerobic, redox-sensitive cells like sperm and Trichomonas, which is susceptible to designed chemical interference for prophylactic contraception. The active thiol in PPC inactivates sperm and Trichomonas via interference with crucial sulfhydryl-disulfide based reactions, e.g. hexokinase activation in human sperm. In comparison to non-specific surfactant action of OTC spermicide nonoxynol-9, the action of thiol-active PPC is apparently much more specific, potent and safe. PPC presents a proof-of-concept for prophylactic contraception via manipulation of thiols in vagina for selective targeting of sperm and Trichomonas, and qualifies as a promising lead for the development of dually protective vaginal-contraceptive|
|URI:||PLoS ONE 8(6): e67365.|
|Appears in Collections:||Endocrinology|
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