Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs and NtRTIs) began in the 1980s when the AIDS epidemic hit Western societies.
NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV).
The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV.
Subsequently, the generated DNA is translocated into the nucleus of the host cell where it is integrated in its genome by the retroviral integrase.
[8] The smaller subunit, called p51, is 440 amino acid long and it is considered to stabilize the heterodimer but also it may take part in the binding of the tRNA primer.
[7][8][9] Activation of nucleoside and nucleotide reverse-transcriptase inhibitors is primarily dependent on cellular entry by passive diffusion or carrier-mediated transport.
[10] This stepwise activation process occurs inside the cell and is mediated by a coordinated series of enzymes.
[11] The first, and often rate limiting, phosphorylation step (for nucleoside analogues) are most commonly catalyzed by deoxynucleoside kinases.
[15] In 1974 zidovudine was reported to have activity against retroviruses and was subsequently re-screened as an antiviral when the AIDS epidemic hit Western societies during the mid-1980s.
[13][15] However, zidovudine is relatively toxic since it is converted into the triphosphate by the cellular enzymes and therefore it is activated in uninfected cells.
[9] Three years after the synthesis of zidovudine, Jerome Horwitz and his colleagues in Chicago prepared another dideoxynucleoside now known as zalcitabine (ddC).
[16] Zalcitabine is a synthetic pyrimidine nucleoside analogue, structurally related to deoxycytidine, in which the 3´-hydroxyl group of the ribose sugar moiety is substituted with hydrogen.
[16] It was initially synthesized as a racemic mixture (BCH-189) and analysis showed that both positive and negative enantiomers of BCH-189 (2',3'-dideoxy-3'-thiacytidine) had in vitro activity against HIV.
The 3' carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom because it had greater anti-HIV activity and is less toxic than the positive enantiomer.
Insertion of a cyclopropyl group on its 6-amino nitrogen of the adenine ring increased lipophilicity and thus enhanced brain penetration.
Carbovir is a related guanosine analogue that had poor oral bioavailability and thus was withdrawn from clinical development.
The acyclic nature of the compound and its phosphonate moiety are unique structural features among the approved NRTIs.
[24] Tenofovir DF was the first nucleotide reverse-transcriptase inhibitor approved by the FDA for the treatment of HIV-1 infection in October 2001.
[18][23] u c l e o s i d e r u g ({[(2R)-1-(6-amino-9H- purin-9-yl)propan-2-yl]oxy}methyl) phosphonic acid 3´Azido-2´,3´-dideoxythymidine, azidothymidine (AZT) 2´,3´-Didehydro-2´,3´-dideoxythymidine (d4T) (-)-ß-L-3´-thia-2´,3´-dideoxy-5-fluorocytidine ((-)FTC) 2´,3´-Dideoxy-3´-thiacytidine (3TC) 2´,3´-Dideoxycytidine (ddC) 2´,3´-Dideoxyinosine (ddI) (4-(2-amino-6-(cyclopropylamino)- 9H-purin-9yl) cyclopent-2enyl)methanol(ABC)
[27] The mutation causes a steric hindrance that can exclude certain drugs, for example lamivudine, from being incorporated during reverse transcription.
The main reasons for continuing the search for new NRTIs against HIV-1 are to decrease toxicity, increase efficiency against resistant viruses, and simplify anti-HIV-1 treatment.
[21] Even though apricitabine is a little less potent in vitro compared to some other NRTIs, it maintains its activity against a broad spectrum of HIV-1 variants with NRTI resistance mutations.
[6] Clinical trials of elvucitabine are on hold, because it has shown bone marrow suppression in some patients, with CD4+ cell numbers dropping as early as two days after initiation of dosing.
Some of the NRTIs that are in development exhibit various attractive pharmacological properties that could make them desirable for the treatment of patients in need of new agents.
