Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA
The acyclic adenosine analogue ( S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured Plasm...
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| Veröffentlicht in: | Molecular and biochemical parasitology 1991-07, Vol.47 (1), p.43-50 |
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| creator | de Vries, Erik Stam, Jeanette G. Franssen, Frits F.J. Nieuwenhuijs, Hans Chavalitshewinkoon, Porntip de Clercq, Erik Prosper Overdulve, J. van der Vliet, Peter C. |
| description | The acyclic adenosine analogue (
S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured
Plasmodium falciparum. Strong inhibition was observed by HPMPA (ID
50 = 47 nM) at concentrations more than 1000-fold less than the cytotoxic dose for human cells. 3-deaza-HPMPA was even more strongly inhibitory (ID
50 = 8 nM), whereas several other acyclic nucleosides were not effective. In mice infected with
Plasmodium berghei, increase of parasitaemia can be blocked for 4–6 days by a single injection of HPMPA. Repeated drug administration blocks parasite growth for prolonged periods at doses that are clinically feasible. We also determined the inhibition of several purified
Plasmodium DNA polymerases by diphosphorylated HPMPA (HPMPApp). DNA polymerase α-like enzymes of
P. falciparum and
P. berghei are inhibited with an IC
50 = 40 μM and a γ-like DNA polymerase from
P. falciparum is even 40-fold more sensitive to the drug. The inhibition by HPMPApp is competitive with dATP, strongly suggesting that
Plasmodium DNA polymerases are targets for this class of nucleotide analogue. |
| doi_str_mv | 10.1016/0166-6851(91)90146-W |
| format | Article |
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S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured
Plasmodium falciparum. Strong inhibition was observed by HPMPA (ID
50 = 47 nM) at concentrations more than 1000-fold less than the cytotoxic dose for human cells. 3-deaza-HPMPA was even more strongly inhibitory (ID
50 = 8 nM), whereas several other acyclic nucleosides were not effective. In mice infected with
Plasmodium berghei, increase of parasitaemia can be blocked for 4–6 days by a single injection of HPMPA. Repeated drug administration blocks parasite growth for prolonged periods at doses that are clinically feasible. We also determined the inhibition of several purified
Plasmodium DNA polymerases by diphosphorylated HPMPA (HPMPApp). DNA polymerase α-like enzymes of
P. falciparum and
P. berghei are inhibited with an IC
50 = 40 μM and a γ-like DNA polymerase from
P. falciparum is even 40-fold more sensitive to the drug. The inhibition by HPMPApp is competitive with dATP, strongly suggesting that
Plasmodium DNA polymerases are targets for this class of nucleotide analogue.</description><identifier>ISSN: 0166-6851</identifier><identifier>EISSN: 1872-9428</identifier><identifier>DOI: 10.1016/0166-6851(91)90146-W</identifier><identifier>PMID: 1857384</identifier><identifier>CODEN: MBIPDP</identifier><language>eng</language><publisher>Shannon: Elsevier B.V</publisher><subject>Acyclic nucleoside ; Adenine - analogs & derivatives ; Adenine - pharmacology ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiparasitic agents ; Antiprotozoal Agents - pharmacology ; Binding, Competitive ; Biological and medical sciences ; Cell Line ; Deoxyadenine Nucleotides - pharmacology ; DNA polymerase inhibitor ; Erythrocytes - drug effects ; Erythrocytes - parasitology ; HPMPA ; Humans ; Malaria ; Malaria - drug therapy ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Nucleic Acid Synthesis Inhibitors ; Organophosphonates ; Organophosphorus Compounds - pharmacology ; Pharmacology. Drug treatments ; Plasmodium berghei ; Plasmodium berghei - drug effects ; Plasmodium berghei - enzymology ; Plasmodium berghei - growth & development ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - enzymology ; Plasmodium falciparum - growth & development ; Tropical medicine</subject><ispartof>Molecular and biochemical parasitology, 1991-07, Vol.47 (1), p.43-50</ispartof><rights>1991</rights><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-93d946dbcdd04f176765caecf35d5ed239ef2fa23dee9ef6c8da32f03e7a19c33</citedby><cites>FETCH-LOGICAL-c417t-93d946dbcdd04f176765caecf35d5ed239ef2fa23dee9ef6c8da32f03e7a19c33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/016668519190146W$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5075784$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1857384$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Vries, Erik</creatorcontrib><creatorcontrib>Stam, Jeanette G.</creatorcontrib><creatorcontrib>Franssen, Frits F.J.</creatorcontrib><creatorcontrib>Nieuwenhuijs, Hans</creatorcontrib><creatorcontrib>Chavalitshewinkoon, Porntip</creatorcontrib><creatorcontrib>de Clercq, Erik</creatorcontrib><creatorcontrib>Prosper Overdulve, J.</creatorcontrib><creatorcontrib>van der Vliet, Peter C.</creatorcontrib><title>Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA</title><title>Molecular and biochemical parasitology</title><addtitle>Mol Biochem Parasitol</addtitle><description>The acyclic adenosine analogue (
S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured
Plasmodium falciparum. Strong inhibition was observed by HPMPA (ID
50 = 47 nM) at concentrations more than 1000-fold less than the cytotoxic dose for human cells. 3-deaza-HPMPA was even more strongly inhibitory (ID
50 = 8 nM), whereas several other acyclic nucleosides were not effective. In mice infected with
Plasmodium berghei, increase of parasitaemia can be blocked for 4–6 days by a single injection of HPMPA. Repeated drug administration blocks parasite growth for prolonged periods at doses that are clinically feasible. We also determined the inhibition of several purified
Plasmodium DNA polymerases by diphosphorylated HPMPA (HPMPApp). DNA polymerase α-like enzymes of
P. falciparum and
P. berghei are inhibited with an IC
50 = 40 μM and a γ-like DNA polymerase from
P. falciparum is even 40-fold more sensitive to the drug. The inhibition by HPMPApp is competitive with dATP, strongly suggesting that
Plasmodium DNA polymerases are targets for this class of nucleotide analogue.</description><subject>Acyclic nucleoside</subject><subject>Adenine - analogs & derivatives</subject><subject>Adenine - pharmacology</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiparasitic agents</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Deoxyadenine Nucleotides - pharmacology</subject><subject>DNA polymerase inhibitor</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - parasitology</subject><subject>HPMPA</subject><subject>Humans</subject><subject>Malaria</subject><subject>Malaria - drug therapy</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Nucleic Acid Synthesis Inhibitors</subject><subject>Organophosphonates</subject><subject>Organophosphorus Compounds - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Plasmodium berghei</subject><subject>Plasmodium berghei - drug effects</subject><subject>Plasmodium berghei - enzymology</subject><subject>Plasmodium berghei - growth & development</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Plasmodium falciparum - growth & development</subject><subject>Tropical medicine</subject><issn>0166-6851</issn><issn>1872-9428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkV1rFDEUhoModVv9BwpzIVIvRpPJ1-RGWOpHC1X3QullyCQn3cjMZE1mlf33ZjpL9UohISe8z3k5nBehZwS_JpiIN-WKWrScnCvySmHCRH3zAK1IK5tasaZ9iFb3yGN0mvN3jDGXQpygE9JySVu2QuPVuA1dmEIcq-iraQvVbYq_pu382_QmD9GF_VB509uwM6mUZnR_Kx2k2y2Eqjvcdb_7vK52sT8MkEyGKiz2MVWXm0-b9RP0qDhleHp8z9C3D--_XlzW118-Xl2sr2vLiJxqRZ1iwnXWOcw8kUIKbg1YT7nj4BqqwDfeNNQBlFLY1hnaeExBGqIspWfo5eK7S_HHHvKkh5At9L0ZIe6zbrHElLH2vyDhSmHGZAHZAtoUc07g9S6FwaSDJljPeeh52XpetlblzHnom9L2_Oi_7wZwf5qWAIr-4qibbE3vkxltyPcYx5LLO-ztgkFZ2s8ASWcbYLTgQgI7aRfDv-f4DQohqEE</recordid><startdate>19910701</startdate><enddate>19910701</enddate><creator>de Vries, Erik</creator><creator>Stam, Jeanette G.</creator><creator>Franssen, Frits F.J.</creator><creator>Nieuwenhuijs, Hans</creator><creator>Chavalitshewinkoon, Porntip</creator><creator>de Clercq, Erik</creator><creator>Prosper Overdulve, J.</creator><creator>van der Vliet, Peter C.</creator><general>Elsevier B.V</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>M7N</scope><scope>7X8</scope></search><sort><creationdate>19910701</creationdate><title>Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA</title><author>de Vries, Erik ; Stam, Jeanette G. ; Franssen, Frits F.J. ; Nieuwenhuijs, Hans ; Chavalitshewinkoon, Porntip ; de Clercq, Erik ; Prosper Overdulve, J. ; van der Vliet, Peter C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-93d946dbcdd04f176765caecf35d5ed239ef2fa23dee9ef6c8da32f03e7a19c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Acyclic nucleoside</topic><topic>Adenine - analogs & derivatives</topic><topic>Adenine - pharmacology</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiparasitic agents</topic><topic>Antiprotozoal Agents - pharmacology</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Deoxyadenine Nucleotides - pharmacology</topic><topic>DNA polymerase inhibitor</topic><topic>Erythrocytes - drug effects</topic><topic>Erythrocytes - parasitology</topic><topic>HPMPA</topic><topic>Humans</topic><topic>Malaria</topic><topic>Malaria - drug therapy</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Nucleic Acid Synthesis Inhibitors</topic><topic>Organophosphonates</topic><topic>Organophosphorus Compounds - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Plasmodium berghei</topic><topic>Plasmodium berghei - drug effects</topic><topic>Plasmodium berghei - enzymology</topic><topic>Plasmodium berghei - growth & development</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Plasmodium falciparum - growth & development</topic><topic>Tropical medicine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>de Vries, Erik</creatorcontrib><creatorcontrib>Stam, Jeanette G.</creatorcontrib><creatorcontrib>Franssen, Frits F.J.</creatorcontrib><creatorcontrib>Nieuwenhuijs, Hans</creatorcontrib><creatorcontrib>Chavalitshewinkoon, Porntip</creatorcontrib><creatorcontrib>de Clercq, Erik</creatorcontrib><creatorcontrib>Prosper Overdulve, J.</creatorcontrib><creatorcontrib>van der Vliet, Peter C.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular and biochemical parasitology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de Vries, Erik</au><au>Stam, Jeanette G.</au><au>Franssen, Frits F.J.</au><au>Nieuwenhuijs, Hans</au><au>Chavalitshewinkoon, Porntip</au><au>de Clercq, Erik</au><au>Prosper Overdulve, J.</au><au>van der Vliet, Peter C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA</atitle><jtitle>Molecular and biochemical parasitology</jtitle><addtitle>Mol Biochem Parasitol</addtitle><date>1991-07-01</date><risdate>1991</risdate><volume>47</volume><issue>1</issue><spage>43</spage><epage>50</epage><pages>43-50</pages><issn>0166-6851</issn><eissn>1872-9428</eissn><coden>MBIPDP</coden><abstract>The acyclic adenosine analogue (
S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured
Plasmodium falciparum. Strong inhibition was observed by HPMPA (ID
50 = 47 nM) at concentrations more than 1000-fold less than the cytotoxic dose for human cells. 3-deaza-HPMPA was even more strongly inhibitory (ID
50 = 8 nM), whereas several other acyclic nucleosides were not effective. In mice infected with
Plasmodium berghei, increase of parasitaemia can be blocked for 4–6 days by a single injection of HPMPA. Repeated drug administration blocks parasite growth for prolonged periods at doses that are clinically feasible. We also determined the inhibition of several purified
Plasmodium DNA polymerases by diphosphorylated HPMPA (HPMPApp). DNA polymerase α-like enzymes of
P. falciparum and
P. berghei are inhibited with an IC
50 = 40 μM and a γ-like DNA polymerase from
P. falciparum is even 40-fold more sensitive to the drug. The inhibition by HPMPApp is competitive with dATP, strongly suggesting that
Plasmodium DNA polymerases are targets for this class of nucleotide analogue.</abstract><cop>Shannon</cop><pub>Elsevier B.V</pub><pmid>1857384</pmid><doi>10.1016/0166-6851(91)90146-W</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0166-6851 |
| ispartof | Molecular and biochemical parasitology, 1991-07, Vol.47 (1), p.43-50 |
| issn | 0166-6851 1872-9428 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_80703448 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Acyclic nucleoside Adenine - analogs & derivatives Adenine - pharmacology Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiparasitic agents Antiprotozoal Agents - pharmacology Binding, Competitive Biological and medical sciences Cell Line Deoxyadenine Nucleotides - pharmacology DNA polymerase inhibitor Erythrocytes - drug effects Erythrocytes - parasitology HPMPA Humans Malaria Malaria - drug therapy Medical sciences Mice Mice, Inbred BALB C Nucleic Acid Synthesis Inhibitors Organophosphonates Organophosphorus Compounds - pharmacology Pharmacology. Drug treatments Plasmodium berghei Plasmodium berghei - drug effects Plasmodium berghei - enzymology Plasmodium berghei - growth & development Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - enzymology Plasmodium falciparum - growth & development Tropical medicine |
| title | Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA |
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