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David Wiemer

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Dr. Lavkush Dwivedi

Bundelkhand University, JHANSI

Slobodan Petrovic

University of Belgrade

Ana Paula Peron

UNIVERSIDADE FEDERAL DO PIAUÍ (BRAZIL)

Elisangela Dusman

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Papers by David Wiemer

$Research paper thumbnail of Identification of light-independent inhibition of human immunodeficiency virus-1 infection through bioguided fractionation of Hypericum perforatum$

Identification of light-independent inhibition of human immunodeficiency virus-1 infection through bioguided fractionation of Hypericum perforatum

Virology …, 2009

Background: Light-dependent activities against enveloped viruses in St. John's Wort (Hypericum pe... more Background: Light-dependent activities against enveloped viruses in St. John's Wort (Hypericum perforatum) extracts have been extensively studied. In contrast, light-independent antiviral activity from this species has not been investigated. Results: Here, we identify the light-independent inhibition of human immunodeficiency virus-1 (HIV-1) by highly purified fractions of chloroform extracts of H. perforatum. Both cytotoxicity and antiviral activity were evident in initial chloroform extracts, but bioassay-guided fractionation produced fractions that inhibited HIV-1 with little to no cytotoxicity. Separation of these two biological activities has not been reported for constituents responsible for the lightdependent antiviral activities. Antiviral activity was associated with more polar subfractions. GC/MS analysis of the two most active subfractions identified 3-hydroxy lauric acid as predominant in one fraction and 3-hydroxy myristic acid as predominant in the other. Synthetic 3-hydroxy lauric acid inhibited HIV infectivity without cytotoxicity, suggesting that this modified fatty acid is likely responsible for observed antiviral activity present in that fraction. As production of 3hydroxy fatty acids by plants remains controversial, H. perforatum seedlings were grown sterilely and evaluated for presence of 3-hydroxy fatty acids by GC/MS. Small quantities of some 3-hydroxy fatty acids were detected in sterile plants, whereas different 3-hydroxy fatty acids were detected in our chloroform extracts or field-grown material. Conclusion: Through bioguided fractionation, we have identified that 3-hydroxy lauric acid found in field grown Hypericum perforatum has anti-HIV activity. This novel anti-HIV activity can be potentially developed into inexpensive therapies, expanding the current arsenal of anti-retroviral agents.

Synthesis of aromatic phosphates via cycloaddition of phosphate dienes

Tetrahedron Letters, 2005

Structure of a 2'-oxo-8.1'-neolignan

Acta Crystallographica Section C Crystal Structure Communications, 1993

?-Trialkylsilylketones from ?-bromoketones: utilization of a 1,3-O to C silyl migration

Journal of the Chemical Society, Chemical Communications, 1985

A new route. from a-bromoketones to a-trialkylsilylketones has been developed which demonstrates ... more

Sythesis and biological evaluation of a phosphonate phosphoantigen prodrug

Phosphorus, Sulfur, and Silicon and the Related Elements, 2014

ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more

Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

Chemistry & biology, Jan 14, 2014

Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...

EDC-mediated condensations of 1-chloro-5-hydrazino-9,10-anthracenedione, 1-hydrazino-9,10-anthracenedione, and the corresponding anthrapyrazoles

Tetrahedron Letters, 2004

The EDC-mediated condensation of 1-chloro-5-hydrazino-9,10-anthracenedione afforded an N-1 acyl a... more The EDC-mediated condensation of 1-chloro-5-hydrazino-9,10-anthracenedione afforded an N-1 acyl anthrapyrazole instead of the expected hydrazide. The regiochemistry of the N-acyl substituent was assigned on the basis of an extensive set of NMR experiments, and identification of this isomer suggests a reaction sequence based on initial acylation and subsequent cyclization. In contrast, the parallel reaction of 1-hydrazino-9,10-anthracenedione proceeded to afford the expected hydrazide.

Erratum to “Synthesis of aromatic phosphates via cycloaddition of phosphate dienes”

Tetrahedron Letters, 2006

The Publisher regrets that an incomplete Scheme 4 was published on page 7586 of the above paper i... more

Regioselective ring-closing metathesis on terpenoid acrylates and acrylamides

Tetrahedron Letters, 2001

A series of acrylate esters was prepared by treatment of representative terpenoid aldehydes with ... more A series of acrylate esters was prepared by treatment of representative terpenoid aldehydes with allyl or vinyl magnesium bromide followed by reaction with acryloyl chloride. In all cases, ring-closing metathesis (RCM) resulted in regioselective formation of unsaturated lactones through metathesis of the acrylate and terminal olefins. After condensation of farnesal with a primary amine, a parallel series of reactions led to formation of the corresponding lactam.

Phospholipase a1 Activity and Catalytic Mechanism of Pancreatic Cholesterol Esterase

Phosphorus, Sulfur, and Silicon and the Related Elements, 1990

The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by usin... more The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by using lipid p-nitrophenyl esters and thiophospholipids as substrates. The rate of CEase-catalyzed hydrolyses of p-nitrophenyl esters is highest for substrates that have fatty acyl chains of intermediate length, while solvent isotope effects decrease with increasing chain length. Nucleophilic trapping experiments indicate that kcat for these substrates is

A new synthesis of .beta.-keto phosphonates and .beta.-keto silanes

The Journal of Organic Chemistry, 1986

acetonitrile, according to the general procedure, a t a potential maintained a t +1.0 V. On worku... more acetonitrile, according to the general procedure, a t a potential maintained a t +1.0 V. On workup, a mixture of brugierol and isobrugierol was isolated in a ratio of 5842 (5 mg, 17%) together with 3, X = H, Y = OSiMe,(t-Bu), as a mixture of cis and trans isomers in a ratio of 3862 (26 mg, 39 % ) as determined by 'H NMR analysis.

Diastereoselective Vinyl Phosphate/β-Keto Phosphonate Rearrangements

The Journal of Organic Chemistry, 1996

Rearrangements of Nonracemic Vinyl Phosphates to .beta.-Keto Phosphonates

The Journal of Organic Chemistry, 1994

Stereoselective Synthesis of (+)-Avarol, (+)-Avarone, and Some Nonracemic Analogues

The Journal of Organic Chemistry, 1996

Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Mies... more Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Miescher ketone is described. This synthetic sequence provides convenient access to the natural enantiomers and, based on comparison of the optical rotation of synthetic avarol dimethyl ether with literature data, affords material of significantly higher optical rotation than a natural source. Similar synthetic strategies have been used to obtain several related compounds, including a decalin bearing an exocyclic olefin and a highly substituted cyclohexane, that can be viewed as hybrids of the trans-fused avarol and cis-fused arenarol skeletons.

The intramolecular Wadsworth-Emmons condensation of .gamma.-(acyloxy)-.beta.-ketophosphonates. A new route to 3(2H)-furanones

The Journal of Organic Chemistry, 1986

ABSTRACT

Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

by Jose Yu and David Wiemer

Bioorganic & Medicinal Chemistry, 2008

Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically... more Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone disease. Because many of their effects may be mediated by depletion of geranylgeranyl diphosphate, our group has sought compounds that do this more directly through inhibition of geranylgeranyl diphosphate synthase and we have discovered a number of isoprenoid-containing bisphosphonates that selectively inhibit this enzyme. These compounds have a high negative charge at physiological pH which is necessary for inhibition of the enzyme but may limit their ability to enter cells. Therefore, chemical modifications that mask this charge may enhance their cellular potency. We now have synthesized novel pivaloyloxymethyl-modified isoprenoid bisphosphonates and investigated their ability to inhibit protein geranylgeranylation within cells. We have found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increases their potency towards cellular geranylgeranylation even though this modification decreases their in vitro inhibition of geranylgeranyl diphosphate synthase. Pivaloyloxymethyl modifications more effectively increase the cellular activity of the more polar isoprenoid bisphosphonates. These results reveal structural relationships between in vitro and cellular activity which may serve as the basis for future development of more potent and/or druglike inhibitors of geranylgeranyl diphosphate synthase.

Synthesis and structure–activity studies of schweinfurthin B analogs: Evidence for the importance of a D-ring hydrogen bond donor in expression of differential cytotoxicity

Bioorganic & Medicinal Chemistry, 2006

The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were ... more The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop structure-activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a common left-half hexahydroxanthene ring system and an aromatic right-half with varied substituents. The synthesis involves penultimate Horner-Wadsworth-Emmons coupling of one of several right-half phosphonates with the aldehyde comprising the left-half of 3-deoxyschweinfurthin B. Preparation of the requisite phosphonates, and the respective stilbenes, as well as the cytotoxicity profiles of these new compounds in the National Cancer InstituteÕs 60 cell-line anticancer screen is described. Several of these analogs displayed cytotoxicity patterns well-correlated with the natural product and differences in activity of $10 3 across the various cell lines. Together, these assay results indicate the importance of at least one free phenol group on the aromatic D-ring of this system for differential cytotoxicity.

Phosphonate Analogues of Cytosine Arabinoside Monophosphate

Phosphorus, Sulfur, and Silicon and the Related Elements, 2002

ABSTRACT Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the... more

Sythesis and biological evaluation of a phosphonate phosphoantigen prodrug

by Olga Vinogradova and David Wiemer

Phosphorus, Sulfur, and Silicon and the Related Elements, 2014

ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more

Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

by Xiaochen Lin, Olga Vinogradova, and David Wiemer

Chemistry & biology, Jan 14, 2014

Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...

$Research paper thumbnail of Identification of light-independent inhibition of human immunodeficiency virus-1 infection through bioguided fractionation of Hypericum perforatum$

Identification of light-independent inhibition of human immunodeficiency virus-1 infection through bioguided fractionation of Hypericum perforatum

Virology …, 2009

Background: Light-dependent activities against enveloped viruses in St. John's Wort (Hypericum pe... more Background: Light-dependent activities against enveloped viruses in St. John's Wort (Hypericum perforatum) extracts have been extensively studied. In contrast, light-independent antiviral activity from this species has not been investigated. Results: Here, we identify the light-independent inhibition of human immunodeficiency virus-1 (HIV-1) by highly purified fractions of chloroform extracts of H. perforatum. Both cytotoxicity and antiviral activity were evident in initial chloroform extracts, but bioassay-guided fractionation produced fractions that inhibited HIV-1 with little to no cytotoxicity. Separation of these two biological activities has not been reported for constituents responsible for the lightdependent antiviral activities. Antiviral activity was associated with more polar subfractions. GC/MS analysis of the two most active subfractions identified 3-hydroxy lauric acid as predominant in one fraction and 3-hydroxy myristic acid as predominant in the other. Synthetic 3-hydroxy lauric acid inhibited HIV infectivity without cytotoxicity, suggesting that this modified fatty acid is likely responsible for observed antiviral activity present in that fraction. As production of 3hydroxy fatty acids by plants remains controversial, H. perforatum seedlings were grown sterilely and evaluated for presence of 3-hydroxy fatty acids by GC/MS. Small quantities of some 3-hydroxy fatty acids were detected in sterile plants, whereas different 3-hydroxy fatty acids were detected in our chloroform extracts or field-grown material. Conclusion: Through bioguided fractionation, we have identified that 3-hydroxy lauric acid found in field grown Hypericum perforatum has anti-HIV activity. This novel anti-HIV activity can be potentially developed into inexpensive therapies, expanding the current arsenal of anti-retroviral agents.

Synthesis of aromatic phosphates via cycloaddition of phosphate dienes

Tetrahedron Letters, 2005

Structure of a 2'-oxo-8.1'-neolignan

Acta Crystallographica Section C Crystal Structure Communications, 1993

?-Trialkylsilylketones from ?-bromoketones: utilization of a 1,3-O to C silyl migration

Journal of the Chemical Society, Chemical Communications, 1985

A new route. from a-bromoketones to a-trialkylsilylketones has been developed which demonstrates ... more

Sythesis and biological evaluation of a phosphonate phosphoantigen prodrug

Phosphorus, Sulfur, and Silicon and the Related Elements, 2014

ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more

Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

Chemistry & biology, Jan 14, 2014

Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...

EDC-mediated condensations of 1-chloro-5-hydrazino-9,10-anthracenedione, 1-hydrazino-9,10-anthracenedione, and the corresponding anthrapyrazoles

Tetrahedron Letters, 2004

The EDC-mediated condensation of 1-chloro-5-hydrazino-9,10-anthracenedione afforded an N-1 acyl a... more The EDC-mediated condensation of 1-chloro-5-hydrazino-9,10-anthracenedione afforded an N-1 acyl anthrapyrazole instead of the expected hydrazide. The regiochemistry of the N-acyl substituent was assigned on the basis of an extensive set of NMR experiments, and identification of this isomer suggests a reaction sequence based on initial acylation and subsequent cyclization. In contrast, the parallel reaction of 1-hydrazino-9,10-anthracenedione proceeded to afford the expected hydrazide.

Erratum to “Synthesis of aromatic phosphates via cycloaddition of phosphate dienes”

Tetrahedron Letters, 2006

The Publisher regrets that an incomplete Scheme 4 was published on page 7586 of the above paper i... more

Regioselective ring-closing metathesis on terpenoid acrylates and acrylamides

Tetrahedron Letters, 2001

A series of acrylate esters was prepared by treatment of representative terpenoid aldehydes with ... more A series of acrylate esters was prepared by treatment of representative terpenoid aldehydes with allyl or vinyl magnesium bromide followed by reaction with acryloyl chloride. In all cases, ring-closing metathesis (RCM) resulted in regioselective formation of unsaturated lactones through metathesis of the acrylate and terminal olefins. After condensation of farnesal with a primary amine, a parallel series of reactions led to formation of the corresponding lactam.

Phospholipase a1 Activity and Catalytic Mechanism of Pancreatic Cholesterol Esterase

Phosphorus, Sulfur, and Silicon and the Related Elements, 1990

The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by usin... more The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by using lipid p-nitrophenyl esters and thiophospholipids as substrates. The rate of CEase-catalyzed hydrolyses of p-nitrophenyl esters is highest for substrates that have fatty acyl chains of intermediate length, while solvent isotope effects decrease with increasing chain length. Nucleophilic trapping experiments indicate that kcat for these substrates is

A new synthesis of .beta.-keto phosphonates and .beta.-keto silanes

The Journal of Organic Chemistry, 1986

acetonitrile, according to the general procedure, a t a potential maintained a t +1.0 V. On worku... more acetonitrile, according to the general procedure, a t a potential maintained a t +1.0 V. On workup, a mixture of brugierol and isobrugierol was isolated in a ratio of 5842 (5 mg, 17%) together with 3, X = H, Y = OSiMe,(t-Bu), as a mixture of cis and trans isomers in a ratio of 3862 (26 mg, 39 % ) as determined by 'H NMR analysis.

Diastereoselective Vinyl Phosphate/β-Keto Phosphonate Rearrangements

The Journal of Organic Chemistry, 1996

Rearrangements of Nonracemic Vinyl Phosphates to .beta.-Keto Phosphonates

The Journal of Organic Chemistry, 1994

Stereoselective Synthesis of (+)-Avarol, (+)-Avarone, and Some Nonracemic Analogues

The Journal of Organic Chemistry, 1996

Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Mies... more Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Miescher ketone is described. This synthetic sequence provides convenient access to the natural enantiomers and, based on comparison of the optical rotation of synthetic avarol dimethyl ether with literature data, affords material of significantly higher optical rotation than a natural source. Similar synthetic strategies have been used to obtain several related compounds, including a decalin bearing an exocyclic olefin and a highly substituted cyclohexane, that can be viewed as hybrids of the trans-fused avarol and cis-fused arenarol skeletons.

The intramolecular Wadsworth-Emmons condensation of .gamma.-(acyloxy)-.beta.-ketophosphonates. A new route to 3(2H)-furanones

The Journal of Organic Chemistry, 1986

ABSTRACT

Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

by Jose Yu and David Wiemer

Bioorganic & Medicinal Chemistry, 2008

Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically... more Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone disease. Because many of their effects may be mediated by depletion of geranylgeranyl diphosphate, our group has sought compounds that do this more directly through inhibition of geranylgeranyl diphosphate synthase and we have discovered a number of isoprenoid-containing bisphosphonates that selectively inhibit this enzyme. These compounds have a high negative charge at physiological pH which is necessary for inhibition of the enzyme but may limit their ability to enter cells. Therefore, chemical modifications that mask this charge may enhance their cellular potency. We now have synthesized novel pivaloyloxymethyl-modified isoprenoid bisphosphonates and investigated their ability to inhibit protein geranylgeranylation within cells. We have found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increases their potency towards cellular geranylgeranylation even though this modification decreases their in vitro inhibition of geranylgeranyl diphosphate synthase. Pivaloyloxymethyl modifications more effectively increase the cellular activity of the more polar isoprenoid bisphosphonates. These results reveal structural relationships between in vitro and cellular activity which may serve as the basis for future development of more potent and/or druglike inhibitors of geranylgeranyl diphosphate synthase.

Synthesis and structure–activity studies of schweinfurthin B analogs: Evidence for the importance of a D-ring hydrogen bond donor in expression of differential cytotoxicity

Bioorganic & Medicinal Chemistry, 2006

The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were ... more The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop structure-activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a common left-half hexahydroxanthene ring system and an aromatic right-half with varied substituents. The synthesis involves penultimate Horner-Wadsworth-Emmons coupling of one of several right-half phosphonates with the aldehyde comprising the left-half of 3-deoxyschweinfurthin B. Preparation of the requisite phosphonates, and the respective stilbenes, as well as the cytotoxicity profiles of these new compounds in the National Cancer InstituteÕs 60 cell-line anticancer screen is described. Several of these analogs displayed cytotoxicity patterns well-correlated with the natural product and differences in activity of $10 3 across the various cell lines. Together, these assay results indicate the importance of at least one free phenol group on the aromatic D-ring of this system for differential cytotoxicity.

Phosphonate Analogues of Cytosine Arabinoside Monophosphate

Phosphorus, Sulfur, and Silicon and the Related Elements, 2002

ABSTRACT Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the... more

Sythesis and biological evaluation of a phosphonate phosphoantigen prodrug

by Olga Vinogradova and David Wiemer

Phosphorus, Sulfur, and Silicon and the Related Elements, 2014

ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more

Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes

by Xiaochen Lin, Olga Vinogradova, and David Wiemer

Chemistry & biology, Jan 14, 2014

Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...