There are many potential and promising male birth control targets.
We work to provide funding support to as many promising non-hormonal, reversible male contraceptives as possible through our funding activities, and we highlight the science that we are supporting on our grantees page. On this page, we share a robust database featuring all of the non-hormonal male birth control targets that have been identified. (For further information about the contraception development pipeline, we recommend visiting Calliope from FHI360’s CTI Exchange.)
Well-studied Targets
This section features male birth control targets that have been investigated and are considered promising leads.
This section features male birth control targets that have been investigated and are considered promising leads.
ABHD2
Abhydrolase domain-containing protein 2
Summary
This is an enzyme expressed in human spermatozoa that is a key controller of sperm hyperactivation, which is a necessary step in allowing sperm to fertilize an egg.
The Science
ABHD2 is an acylglycerol lipase enzyme that catalyzes endo-cannabinoids 1-arachidonoylglycerol (1AG) and 2-arachidonoylglycerol (2AG) only in the presence of progesterone (P4). AGs have been shown to act as inhibitors of CatSper, a sperm-specific calcium channel. Upon P4 stimulation, ABHD2 leads to the activation of CatSper, which results in sperm activation.
Category
Sperm Function
Anticipated User
Unisex
Publications
"Preventing sperm's 'power kick' could be key to unisex contraceptive". Berkeley News. 2016-03-17. Retrieved 2017-09-13.
Mannowetz, Nadja; Miller, Melissa R.; Lishko, Polina V. (2017-05-30). "Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids". Proceedings of the National Academy of Sciences. 114 (22): 5743–5748. doi:10.1073/pnas.1700367114. ISSN 0027-8424. PMC 5465908. PMID 28507119.
Jin S, Zhao G, Li Z, Nishimoto Y, Isohama Y, Shen J, Ito T, Takeya M, Araki K, He P, Yamamura K (Mar 2009). "Age-related pulmonary emphysema in mice lacking alpha/beta hydrolase domain containing 2 gene". Biochemical and Biophysical Research Communications. 380 (2): 419–24.
This is an enzyme expressed in human spermatozoa that is a key controller of sperm hyperactivation, which is a necessary step in allowing sperm to fertilize an egg.
The Science
ABHD2 is an acylglycerol lipase enzyme that catalyzes endo-cannabinoids 1-arachidonoylglycerol (1AG) and 2-arachidonoylglycerol (2AG) only in the presence of progesterone (P4). AGs have been shown to act as inhibitors of CatSper, a sperm-specific calcium channel. Upon P4 stimulation, ABHD2 leads to the activation of CatSper, which results in sperm activation.
Category
Sperm Function
Anticipated User
Unisex
Publications
"Preventing sperm's 'power kick' could be key to unisex contraceptive". Berkeley News. 2016-03-17. Retrieved 2017-09-13.
Mannowetz, Nadja; Miller, Melissa R.; Lishko, Polina V. (2017-05-30). "Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids". Proceedings of the National Academy of Sciences. 114 (22): 5743–5748. doi:10.1073/pnas.1700367114. ISSN 0027-8424. PMC 5465908. PMID 28507119.
Jin S, Zhao G, Li Z, Nishimoto Y, Isohama Y, Shen J, Ito T, Takeya M, Araki K, He P, Yamamura K (Mar 2009). "Age-related pulmonary emphysema in mice lacking alpha/beta hydrolase domain containing 2 gene". Biochemical and Biophysical Research Communications. 380 (2): 419–24.
ALDH1A1
Aldehyde dehydrogenase 1 family, member A1
Summary
Blocking this enzyme could prevent the male body from producing sperm.
The Science
Also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), this is an enzyme that in humans is encoded by the ALDH1A1 gene. ALDH1A2 is an enzyme involved in testicular retinoic acid biosynthesis, that if blocked can arrest spermotogenesis. Small molecule inhibitors of ALDH1A2 are being developed as long-term oral, reversible male contraceptives, based on earlier work on bisdichloroacetyldiamines (BDADs).
Category
Spermatogenesis
Anticipated User
Male
Publications
Pereira F, Rosenmann E, Nylen E, Kaufman M, Pinsky L, Wrogemann K (March 1991). "The 56 kDa androgen binding protein is an aldehyde dehydrogenase". Biochemical and Biophysical Research Communications. 175 (3): 831–8. doi:10.1016/0006-291X(91)91640-X. PMID 1709013.
Hsu LC, Tani K, Fujiyoshi T, Kurachi K, Yoshida A (June 1985). "Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2". Proceedings of the National Academy of Sciences of the United States of America. 82 (11): 3771–5. Bibcode:1985PNAS...82.3771H. doi:10.1073/pnas.82.11.3771. PMC 397869. PMID 2987944.
Blocking this enzyme could prevent the male body from producing sperm.
The Science
Also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), this is an enzyme that in humans is encoded by the ALDH1A1 gene. ALDH1A2 is an enzyme involved in testicular retinoic acid biosynthesis, that if blocked can arrest spermotogenesis. Small molecule inhibitors of ALDH1A2 are being developed as long-term oral, reversible male contraceptives, based on earlier work on bisdichloroacetyldiamines (BDADs).
Category
Spermatogenesis
Anticipated User
Male
Publications
Pereira F, Rosenmann E, Nylen E, Kaufman M, Pinsky L, Wrogemann K (March 1991). "The 56 kDa androgen binding protein is an aldehyde dehydrogenase". Biochemical and Biophysical Research Communications. 175 (3): 831–8. doi:10.1016/0006-291X(91)91640-X. PMID 1709013.
Hsu LC, Tani K, Fujiyoshi T, Kurachi K, Yoshida A (June 1985). "Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2". Proceedings of the National Academy of Sciences of the United States of America. 82 (11): 3771–5. Bibcode:1985PNAS...82.3771H. doi:10.1073/pnas.82.11.3771. PMC 397869. PMID 2987944.
ANT4
Adenine nucleotide translocase 4
Summary
This is the most abundant protein in male germ cell mitochondria, and reducing its presence could make men infertile.
The Science
This facilitates ADP (adenosine diphosphate)/ATP (adenosine triphosphate) exchange across the mitochondrial inner membrane and is exclusively expressed in male germ cells. Ant4 expression is particularly high during male meiosis and is essential for progression of male meiosis. Targeted depletion of Ant4 in mice has resulted in male infertility.
Category
Spermatogenesis
Anticipated User
Male
Publications
Klingenberg M (October 2008). "The ADP and ATP transport in mitochondria and its carrier". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1778 (10): 1978–2021. doi:10.1016/j.bbamem.2008.04.011. PMID 18510943.
Kunji ER, Aleksandrova A, King MS, Majd H, Ashton VL, Cerson E, Springett R, Kibalchenko M, Tavoulari S, Crichton PG, Ruprecht JJ (October 2016). "The transport mechanism of the mitochondrial ADP/ATP carrier". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. Channels and transporters in cell metabolism. 1863 (10): 2379–93.
This is the most abundant protein in male germ cell mitochondria, and reducing its presence could make men infertile.
The Science
This facilitates ADP (adenosine diphosphate)/ATP (adenosine triphosphate) exchange across the mitochondrial inner membrane and is exclusively expressed in male germ cells. Ant4 expression is particularly high during male meiosis and is essential for progression of male meiosis. Targeted depletion of Ant4 in mice has resulted in male infertility.
Category
Spermatogenesis
Anticipated User
Male
Publications
Klingenberg M (October 2008). "The ADP and ATP transport in mitochondria and its carrier". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1778 (10): 1978–2021. doi:10.1016/j.bbamem.2008.04.011. PMID 18510943.
Kunji ER, Aleksandrova A, King MS, Majd H, Ashton VL, Cerson E, Springett R, Kibalchenko M, Tavoulari S, Crichton PG, Ruprecht JJ (October 2016). "The transport mechanism of the mitochondrial ADP/ATP carrier". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. Channels and transporters in cell metabolism. 1863 (10): 2379–93.
BRDT
BRDT Gene
Summary
This is a protein coding gene, and inhibiting its function could cause a reversible reduction of sperm production and quality.
The Science
BRDT is a transcriptional regulator that belongs to the bromodomain and extra-terminal (BET) subfamily of epigenetic reader proteins. BRDT is predominantly expressed in the testis and is also observed in the mouse pituitary gland. BRDT is involved in chromatin organization and transcriptional regulation during spermatogenesis. It is also shown to play a role in scheduling male puberty through the regulation of the pituitary-gonadal axis. BRDT-null male mice are infertile and demonstrate severe reproductive phenotypes. The small molecule, JQ1, is a lead compound in targeting BRDT.
Category
Spermatogenesis, Sperm Function
Anticipated User
Male
Publications
Jones MH, Numata M, Shimane M (Jan 1998). "Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh". Genomics. 45 (3): 529–34. doi:10.1006/geno.1997.5000. PMID 9367677.
Gaucher J, Boussouar F, Montellier E, Curtet S, Buchou T, Bertrand S, Hery P, Jounier S, Depaux A, Vitte AL, Guardiola P, Pernet K, Debernardi A, Lopez F, Holota H, Imbert J, Wolgemuth DJ, Gérard M, Rousseaux S, Khochbin S (2012). "Bromodomain-dependent stage-specific male genome programming by Brdt". EMBO J. 31 (19): 3809–20. doi:10.1038/emboj.2012.233. PMC 3463845. PMID 22922464.
Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
This is a protein coding gene, and inhibiting its function could cause a reversible reduction of sperm production and quality.
The Science
BRDT is a transcriptional regulator that belongs to the bromodomain and extra-terminal (BET) subfamily of epigenetic reader proteins. BRDT is predominantly expressed in the testis and is also observed in the mouse pituitary gland. BRDT is involved in chromatin organization and transcriptional regulation during spermatogenesis. It is also shown to play a role in scheduling male puberty through the regulation of the pituitary-gonadal axis. BRDT-null male mice are infertile and demonstrate severe reproductive phenotypes. The small molecule, JQ1, is a lead compound in targeting BRDT.
Category
Spermatogenesis, Sperm Function
Anticipated User
Male
Publications
Jones MH, Numata M, Shimane M (Jan 1998). "Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh". Genomics. 45 (3): 529–34. doi:10.1006/geno.1997.5000. PMID 9367677.
Gaucher J, Boussouar F, Montellier E, Curtet S, Buchou T, Bertrand S, Hery P, Jounier S, Depaux A, Vitte AL, Guardiola P, Pernet K, Debernardi A, Lopez F, Holota H, Imbert J, Wolgemuth DJ, Gérard M, Rousseaux S, Khochbin S (2012). "Bromodomain-dependent stage-specific male genome programming by Brdt". EMBO J. 31 (19): 3809–20. doi:10.1038/emboj.2012.233. PMC 3463845. PMID 22922464.
Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
CatSper
Catsper Channels
Summary
These channels have different functions in humans, with a few of them specifically related to sperm. Inhibiting their performance could lead to male infertility.
The Science
CatSper is a calcium-selective ion channel confined to the tail of mature sperm. CatSper is required for hyperactivated sperm motility and thus fertilization. CatSper is encoded by four distinct genes, CatSper1-4, which form the pore of the channel. Additional subunits are also required for proper assembly of the channel along a quadrilateral complex from the sperm midpiece to end of the tail. Mutant CatSper genes in humans are associated with male infertility. Small molecule screens have yielded CatSper blockers. These require refining for potency, specificity, and pharmacokinetics.
Category
Sperm Function
Anticipated User
Unisex
Publications
Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, et al. (January 2007). "All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility". Proceedings of the National Academy of Sciences of the United States of America. 104 (4): 1219–23. doi:10.1073/pnas.0610286104. PMC 1770895. PMID 17227845.
Chung JJ, Navarro B, Krapivinsky G, Krapivinsky L, Clapham DE (January 2011). "A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa". Nature Communications. 2 (1): 153. Bibcode:2011NatCo...2..153C. doi:10.1038/ncomms1153. PMC 3999383. PMID 21224844. Lishko PV, Botchkina IL, Kirichok Y (March 2011). "Progesterone activates the principal Ca2+ channel of human sperm". Nature. 471 (7338): 387–91. Bibcode:2011Natur.471..387L. doi:10.1038/nature09767. PMID 21412339. S2CID 4340309.
These channels have different functions in humans, with a few of them specifically related to sperm. Inhibiting their performance could lead to male infertility.
The Science
CatSper is a calcium-selective ion channel confined to the tail of mature sperm. CatSper is required for hyperactivated sperm motility and thus fertilization. CatSper is encoded by four distinct genes, CatSper1-4, which form the pore of the channel. Additional subunits are also required for proper assembly of the channel along a quadrilateral complex from the sperm midpiece to end of the tail. Mutant CatSper genes in humans are associated with male infertility. Small molecule screens have yielded CatSper blockers. These require refining for potency, specificity, and pharmacokinetics.
Category
Sperm Function
Anticipated User
Unisex
Publications
Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, et al. (January 2007). "All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility". Proceedings of the National Academy of Sciences of the United States of America. 104 (4): 1219–23. doi:10.1073/pnas.0610286104. PMC 1770895. PMID 17227845.
Chung JJ, Navarro B, Krapivinsky G, Krapivinsky L, Clapham DE (January 2011). "A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa". Nature Communications. 2 (1): 153. Bibcode:2011NatCo...2..153C. doi:10.1038/ncomms1153. PMC 3999383. PMID 21224844. Lishko PV, Botchkina IL, Kirichok Y (March 2011). "Progesterone activates the principal Ca2+ channel of human sperm". Nature. 471 (7338): 387–91. Bibcode:2011Natur.471..387L. doi:10.1038/nature09767. PMID 21412339. S2CID 4340309.
EPPIN
Epididymal Protease Inhibitor
Summary
This protein is critical for sperm movement; preventing its proper functioning could prevent sperm from being able to exit the male body.
The Science
Eppin is a sperm surface protein that binds semenogelin (SEMG1) and is critical for the protection of sperm from the enzymatic degradation of the semen coagulum, which frees the spermatozoa for motility and capacitation. Eppin is the contraceptive target for a small organic compound that binds Eppin and inhibits sperm motility. Blocking Eppin has been also shown to inhibit the motility required for fertilization by decreasing the sperm pH and reducing calcium levels.
Category
Sperm Function
Anticipated User
Male
Publications
Silva EJR, Hamil KG, et al. (2012) Characterization of EPPIN's semenogelin I binding site: A contraceptive drug target. Biol Repro 87(3):56, 1-8.
O'Rand MG, Widgren EE, et al. (2006) Eppin: an effective target for male contraception. Mol Cell Endocrinol 250:157-162.
O'Rand MG, Hamil K, Adevai T, Zelinski M. (2018). Inhibition of sperm motility in male macaques with EP055, a potential non-hormonal male contraceptive. PLoS ONE 13(4): e0195953.
This protein is critical for sperm movement; preventing its proper functioning could prevent sperm from being able to exit the male body.
The Science
Eppin is a sperm surface protein that binds semenogelin (SEMG1) and is critical for the protection of sperm from the enzymatic degradation of the semen coagulum, which frees the spermatozoa for motility and capacitation. Eppin is the contraceptive target for a small organic compound that binds Eppin and inhibits sperm motility. Blocking Eppin has been also shown to inhibit the motility required for fertilization by decreasing the sperm pH and reducing calcium levels.
Category
Sperm Function
Anticipated User
Male
Publications
Silva EJR, Hamil KG, et al. (2012) Characterization of EPPIN's semenogelin I binding site: A contraceptive drug target. Biol Repro 87(3):56, 1-8.
O'Rand MG, Widgren EE, et al. (2006) Eppin: an effective target for male contraception. Mol Cell Endocrinol 250:157-162.
O'Rand MG, Hamil K, Adevai T, Zelinski M. (2018). Inhibition of sperm motility in male macaques with EP055, a potential non-hormonal male contraceptive. PLoS ONE 13(4): e0195953.
GAPDHS
Glyceraldehyde 3-phosphate dehydrogenase-S
Summary
This enzyme helps “feed” sperm and is necessary for them to have the energy to swim. Preventing its function could cause male infertility.
The Science
Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDHS) is a sperm specific enzyme, and is part of the metabolic pathway required to convert glucose into ATP (source of energy for sperm). By binding GAPDHS and inhibiting glycolysis, sperm motility is impaired, thus leading to infertility.
Category
Sperm Function
Anticipated User
Male
Publications
Miki K, Qu W, et al. (2004) Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility. Proc Natl Acad Sci USA. 101:16501-16506.
This enzyme helps “feed” sperm and is necessary for them to have the energy to swim. Preventing its function could cause male infertility.
The Science
Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDHS) is a sperm specific enzyme, and is part of the metabolic pathway required to convert glucose into ATP (source of energy for sperm). By binding GAPDHS and inhibiting glycolysis, sperm motility is impaired, thus leading to infertility.
Category
Sperm Function
Anticipated User
Male
Publications
Miki K, Qu W, et al. (2004) Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility. Proc Natl Acad Sci USA. 101:16501-16506.
HIPK4
Summary
The Science
Category
Anticipated User
Publications
The Science
Category
Anticipated User
Publications
IZUMO1
Summary
The Science
Category
Anticipated User
Publications
The Science
Category
Anticipated User
Publications
PPP3CC / PPP3R2
Summary
The Science
Category
Anticipated User
Publications
The Science
Category
Anticipated User
Publications
RAR⍺
Summary
The Science
Category
Anticipated User
Publications
The Science
Category
Anticipated User
Publications
TSSK1/2/6
Summary
The Science
Category
Anticipated User
Publications
The Science
Category
Anticipated User
Publications
Other Targets
This section features the additional targets that have been identified for their potential as male contraceptives but have not been as investigated as other promising leads.
This section features the additional targets that have been identified for their potential as male contraceptives but have not been as investigated as other promising leads.
Spermatogenesis
Sperm Transport
Sperm Motility
Fertilization
Multiple Categories