Designed Chemical Intervention with Thiols for Prophylactic Contraception
IR@CDRI: CSIR-Central Drug Research Institute, Lucknow
View Archive Info| Field | Value | |
| Creator |
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 |
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| Date |
2013-07-05T06:50:00Z
2013-07-05T06:50:00Z 2013 |
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| Identifier |
PLoS ONE 8(6): e67365.
http://hdl.handle.net/123456789/1081 |
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| 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
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938339 bytes
application/pdf |
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| Language |
en
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| Relation |
C.D.R.I. Communication No. 8464
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| Subject |
Sulfhydryls
Hexokinase Microbicidal spermicide Trichomonas vaginalis Contraceptive film |
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| Title |
Designed Chemical Intervention with Thiols for Prophylactic Contraception
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| Type |
Article
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