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4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

Abstract Chagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos neglected tropical diseases
Publication Year Start




PMID- 29281643
OWN - NLM
STAT- In-Data-Review
LR  - 20171227
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Linking)
VI  - 11
IP  - 12
DP  - 2017 Dec
TI  - 4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite 
      relapse in a chronic model and improve cardiac pathology in an acute model of
      Trypanosoma cruzi infection.
PG  - e0006132
LID - 10.1371/journal.pntd.0006132 [doi]
AB  - BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi, is the
      leading cause of heart failure in Latin America. The clinical treatment of Chagas
      disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that
      have variable efficacy against different strains of the parasite and may lead to 
      severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that
      has been exploited for the development of therapeutics for fungal and parasitic
      infections. In a target-based drug discovery program guided by x-ray
      crystallography, we identified the 4-aminopyridyl-based series of CYP51
      inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent
      leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.
      METHODOLOGY/PRINCIPAL FINDINGS: Both acute and chronic animal models infected
      with wild type or transgenic T. cruzi strains were evaluated. There was no
      evidence of toxicity in the 28-day dosing study of uninfected animals, as judged 
      by the monitoring of multiple serum and histological parameters. In two acute
      models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased
      survival of mice, and prevented liver and heart injury. None of the compounds
      produced long term sterile cure. In the less severe acute model using the
      transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug
      withdrawal. In the chronic model, parasitemia fell to a background level and, as 
      evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted
      luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two 
      immunosuppression cycles with cyclophosphamide were required to re-activate the
      parasites. Although no sterile cure was achieved, the suppression of parasitemia 
      in acutely infected mice resulted in drastically reduced inflammation in the
      heart. CONCLUSIONS/SIGNIFICANCE: The positive outcomes achieved in the absence of
      sterile cure suggest that the target product profile in anti-Chagasic drug
      discovery should be revised in favor of safe re-administration of the medication 
      during the lifespan of a Chagas disease patient. A medication that reduces
      parasite burden may halt or slow progression of cardiomyopathy and therefore
      improve both life expectancy and quality of life.
FAU - Calvet, Claudia Magalhaes
AU  - Calvet CM
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
AD  - Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio
      de Janeiro, Rio de Janeiro, Brazil.
FAU - Choi, Jun Yong
AU  - Choi JY
AD  - Department of Chemistry, Scripps Florida, Jupiter, Florida, United States of
      America.
FAU - Thomas, Diane
AU  - Thomas D
AUID- ORCID: http://orcid.org/0000-0003-3101-6606
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Suzuki, Brian
AU  - Suzuki B
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Hirata, Ken
AU  - Hirata K
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Lostracco-Johnson, Sharon
AU  - Lostracco-Johnson S
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - de Mesquita, Liliane Batista
AU  - de Mesquita LB
AD  - Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio
      de Janeiro, Rio de Janeiro, Brazil.
FAU - Nogueira, Alanderson
AU  - Nogueira A
AD  - Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio
      de Janeiro, Rio de Janeiro, Brazil.
FAU - Meuser-Batista, Marcelo
AU  - Meuser-Batista M
AD  - Department of Pathologic Anatomy, Fernandes Figueira Institute (IFF), FIOCRUZ,
      Rio de Janeiro, Rio de Janeiro, Brazil.
FAU - Silva, Tatiana Araujo
AU  - Silva TA
AD  - Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio
      de Janeiro, Rio de Janeiro, Brazil.
FAU - Siqueira-Neto, Jair Lage
AU  - Siqueira-Neto JL
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Roush, William R
AU  - Roush WR
AUID- ORCID: http://orcid.org/0000-0001-9785-5897
AD  - Department of Chemistry, Scripps Florida, Jupiter, Florida, United States of
      America.
FAU - de Souza Pereira, Mirian Claudia
AU  - de Souza Pereira MC
AD  - Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio
      de Janeiro, Rio de Janeiro, Brazil.
FAU - McKerrow, James H
AU  - McKerrow JH
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Podust, Larissa M
AU  - Podust LM
AUID- ORCID: http://orcid.org/0000-0002-8537-8760
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20171227
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
EDAT- 2017/12/28 06:00
MHDA- 2017/12/28 06:00
CRDT- 2017/12/28 06:00
PHST- 2017/10/11 00:00 [received]
PHST- 2017/11/22 00:00 [accepted]
PHST- 2017/12/28 06:00 [entrez]
PHST- 2017/12/28 06:00 [pubmed]
PHST- 2017/12/28 06:00 [medline]
AID - 10.1371/journal.pntd.0006132 [doi]
AID - PNTD-D-17-01639 [pii]
PST - epublish
SO  - PLoS Negl Trop Dis. 2017 Dec 27;11(12):e0006132. doi:
      10.1371/journal.pntd.0006132. eCollection 2017 Dec.