A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium

Anindita Mukerjee, Pinar Iyidogan, Alejandro Castellanos-Gonzalez, José A. Cisneros, Daniel Czyzyk, Amalendu Prakash Ranjan, William L. Jorgensen, A. Clinton White, Jamboor K. Vishwanatha, Karen S. Anderson

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Cryptosporidiosis, a gastrointestinal disease caused by protozoans of the genus Cryptosporidium, is a common cause of diarrheal diseases and often fatal in immunocompromised individuals. Bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis (C. hominis) has been a molecular target for inhibitor design. C. hominis TS-DHFR inhibitors with nM potency at a biochemical level have been developed however drug delivery to achieve comparable antiparasitic activity in Cryptosporidium infected cell culture has been a major hurdle for designing effective therapies. Previous mechanistic and structural studies have identified compound 906 as a nM C. hominis TS-DHFR inhibitor in vitro, having μM antiparasitic activity in cell culture. In this work, proof of concept studies are presented using a nanotherapy approach to improve drug delivery and the antiparasitic activity of 906 in cell culture. We utilized PLGA nanoparticles that were loaded with 906 (NP-906) and conjugated with antibodies to the Cryptosporidium specific protein, CP2, on the nanoparticle surface in order to specifically target the parasite. Our results indicate that CP2 labeled NP-906 (CP2-NP-906) reduces the level of parasites by 200-fold in cell culture, while NP-906 resulted in 4.4-fold decrease. Moreover, the anticryptosporidial potency of 906 improved 15 to 78-fold confirming the utility of the antibody conjugated nanoparticles as an effective drug delivery strategy.

Original languageEnglish
Pages (from-to)2065-2067
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number10
DOIs
StatePublished - 15 Jun 2015

Fingerprint

Cryptosporidium
Cell culture
Antiparasitic Agents
Drug delivery
Folic Acid Antagonists
Cell Culture Techniques
Nanoparticles
Antibodies
Parasites
Cryptosporidiosis
Gastrointestinal Diseases
Pharmaceutical Preparations
thymidylate synthase-dihydrofolate reductase
Proteins

Keywords

  • Cryptosporidium hominis
  • Dihydrofolate reductase
  • Drug delivery
  • Nanoparticle
  • Thymidylate synthase

Cite this

Mukerjee, Anindita ; Iyidogan, Pinar ; Castellanos-Gonzalez, Alejandro ; Cisneros, José A. ; Czyzyk, Daniel ; Ranjan, Amalendu Prakash ; Jorgensen, William L. ; White, A. Clinton ; Vishwanatha, Jamboor K. ; Anderson, Karen S. / A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium. In: Bioorganic and Medicinal Chemistry Letters. 2015 ; Vol. 25, No. 10. pp. 2065-2067.
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A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium. / Mukerjee, Anindita; Iyidogan, Pinar; Castellanos-Gonzalez, Alejandro; Cisneros, José A.; Czyzyk, Daniel; Ranjan, Amalendu Prakash; Jorgensen, William L.; White, A. Clinton; Vishwanatha, Jamboor K.; Anderson, Karen S.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 10, 15.06.2015, p. 2065-2067.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium

AU - Mukerjee, Anindita

AU - Iyidogan, Pinar

AU - Castellanos-Gonzalez, Alejandro

AU - Cisneros, José A.

AU - Czyzyk, Daniel

AU - Ranjan, Amalendu Prakash

AU - Jorgensen, William L.

AU - White, A. Clinton

AU - Vishwanatha, Jamboor K.

AU - Anderson, Karen S.

PY - 2015/6/15

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N2 - Cryptosporidiosis, a gastrointestinal disease caused by protozoans of the genus Cryptosporidium, is a common cause of diarrheal diseases and often fatal in immunocompromised individuals. Bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis (C. hominis) has been a molecular target for inhibitor design. C. hominis TS-DHFR inhibitors with nM potency at a biochemical level have been developed however drug delivery to achieve comparable antiparasitic activity in Cryptosporidium infected cell culture has been a major hurdle for designing effective therapies. Previous mechanistic and structural studies have identified compound 906 as a nM C. hominis TS-DHFR inhibitor in vitro, having μM antiparasitic activity in cell culture. In this work, proof of concept studies are presented using a nanotherapy approach to improve drug delivery and the antiparasitic activity of 906 in cell culture. We utilized PLGA nanoparticles that were loaded with 906 (NP-906) and conjugated with antibodies to the Cryptosporidium specific protein, CP2, on the nanoparticle surface in order to specifically target the parasite. Our results indicate that CP2 labeled NP-906 (CP2-NP-906) reduces the level of parasites by 200-fold in cell culture, while NP-906 resulted in 4.4-fold decrease. Moreover, the anticryptosporidial potency of 906 improved 15 to 78-fold confirming the utility of the antibody conjugated nanoparticles as an effective drug delivery strategy.

AB - Cryptosporidiosis, a gastrointestinal disease caused by protozoans of the genus Cryptosporidium, is a common cause of diarrheal diseases and often fatal in immunocompromised individuals. Bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis (C. hominis) has been a molecular target for inhibitor design. C. hominis TS-DHFR inhibitors with nM potency at a biochemical level have been developed however drug delivery to achieve comparable antiparasitic activity in Cryptosporidium infected cell culture has been a major hurdle for designing effective therapies. Previous mechanistic and structural studies have identified compound 906 as a nM C. hominis TS-DHFR inhibitor in vitro, having μM antiparasitic activity in cell culture. In this work, proof of concept studies are presented using a nanotherapy approach to improve drug delivery and the antiparasitic activity of 906 in cell culture. We utilized PLGA nanoparticles that were loaded with 906 (NP-906) and conjugated with antibodies to the Cryptosporidium specific protein, CP2, on the nanoparticle surface in order to specifically target the parasite. Our results indicate that CP2 labeled NP-906 (CP2-NP-906) reduces the level of parasites by 200-fold in cell culture, while NP-906 resulted in 4.4-fold decrease. Moreover, the anticryptosporidial potency of 906 improved 15 to 78-fold confirming the utility of the antibody conjugated nanoparticles as an effective drug delivery strategy.

KW - Cryptosporidium hominis

KW - Dihydrofolate reductase

KW - Drug delivery

KW - Nanoparticle

KW - Thymidylate synthase

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