Designed Chemical Intervention with Thiols for Prophylactic Contraception.
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 rati...
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doaj-caebfea36bc54710a5767495bec178dd2020-11-25T01:31:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6736510.1371/journal.pone.0067365Designed Chemical Intervention with Thiols for Prophylactic Contraception.Monika SharmaLokesh KumarAshish JainVikas VermaVikas SharmaBhavana KushwahaNand LalLalit KumarTara RawatAnil K DwivediJagdamba P MaikhuriVishnu L SharmaGopal GuptaUnlike 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 37°C in 5 minutes, in vitro. We have thus discovered a common target (reactive thiols) on chiefly-anaerobic, 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.http://europepmc.org/articles/PMC3694959?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Monika Sharma Lokesh Kumar Ashish Jain Vikas Verma Vikas Sharma Bhavana Kushwaha Nand Lal Lalit Kumar Tara Rawat Anil K Dwivedi Jagdamba P Maikhuri Vishnu L Sharma Gopal Gupta |
spellingShingle |
Monika Sharma Lokesh Kumar Ashish Jain Vikas Verma Vikas Sharma Bhavana Kushwaha Nand Lal Lalit Kumar Tara Rawat Anil K Dwivedi Jagdamba P Maikhuri Vishnu L Sharma Gopal Gupta Designed Chemical Intervention with Thiols for Prophylactic Contraception. PLoS ONE |
author_facet |
Monika Sharma Lokesh Kumar Ashish Jain Vikas Verma Vikas Sharma Bhavana Kushwaha Nand Lal Lalit Kumar Tara Rawat Anil K Dwivedi Jagdamba P Maikhuri Vishnu L Sharma Gopal Gupta |
author_sort |
Monika Sharma |
title |
Designed Chemical Intervention with Thiols for Prophylactic Contraception. |
title_short |
Designed Chemical Intervention with Thiols for Prophylactic Contraception. |
title_full |
Designed Chemical Intervention with Thiols for Prophylactic Contraception. |
title_fullStr |
Designed Chemical Intervention with Thiols for Prophylactic Contraception. |
title_full_unstemmed |
Designed Chemical Intervention with Thiols for Prophylactic Contraception. |
title_sort |
designed chemical intervention with thiols for prophylactic contraception. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
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 37°C in 5 minutes, in vitro. We have thus discovered a common target (reactive thiols) on chiefly-anaerobic, 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. |
url |
http://europepmc.org/articles/PMC3694959?pdf=render |
work_keys_str_mv |
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