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Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K-specific inhibition.
Baldwin, Eric T; Götte, Matthias; Tchesnokov, Egor P; Arnold, Eddy; Hagel, Margit; Nichols, Charles; Dossang, Pam; Lamers, Marieke; Wan, Paul; Steinbacher, Stefan; Romero, Donna L.
Afiliación
  • Baldwin ET; ROME Therapeutics, Boston, MA 02215.
  • Götte M; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Tchesnokov EP; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Arnold E; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, 08854.
  • Hagel M; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, 08854.
  • Nichols C; ROME Therapeutics, Boston, MA 02215.
  • Dossang P; Charles River Laboratory, Chesterford Research Park, Saffron Walden CB10 1XL, United Kingdom.
  • Lamers M; Charles River Laboratory, Chesterford Research Park, Saffron Walden CB10 1XL, United Kingdom.
  • Wan P; Charles River Laboratory, Chesterford Research Park, Saffron Walden CB10 1XL, United Kingdom.
  • Steinbacher S; DomainEx, Chesterford Research Park, Saffron Walden CB10 1XL United Kingdom.
  • Romero DL; Charles River Laboratory, Chesterford Research Park, Saffron Walden CB10 1XL, United Kingdom.
Proc Natl Acad Sci U S A ; 119(27): e2200260119, 2022 07 05.
Article en En | MEDLINE | ID: mdl-35771941
ABSTRACT
Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and are derived from ancient integrations of retroviruses into the germline. The biology of HERVs is poorly defined, but there is accumulating evidence supporting pathological roles in diverse diseases, such as cancer, autoimmune, and neurodegenerative diseases. Functional proteins are produced by HERV-encoded genes, including reverse transcriptases (RTs), which could be a contributor to the pathology attributed to aberrant HERV-K expression. To facilitate the discovery and development of HERV-K RT potent and selective inhibitors, we expressed active HERV-K RT and determined the crystal structure of a ternary complex of this enzyme with a double-stranded DNA substrate. We demonstrate a range of RT inhibition with antiretroviral nucleotide analogs, while classic nonnucleoside analogs do not inhibit HERV-K RT. Detailed comparisons of HERV-K RT with other known RTs demonstrate similarities to diverse RT families and a striking similarity to the HIV-1 RT asymmetric heterodimer. Our analysis further reveals opportunities for selective HERV-K RT inhibition.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ADN Polimerasa Dirigida por ARN / Inhibidores de la Transcriptasa Inversa / Retrovirus Endógenos / Antirretrovirales / Descubrimiento de Drogas Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ADN Polimerasa Dirigida por ARN / Inhibidores de la Transcriptasa Inversa / Retrovirus Endógenos / Antirretrovirales / Descubrimiento de Drogas Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2022 Tipo del documento: Article