Acyclovir 2013.03.15 Lee, sang-hwi

Reverse transcription (역전사) Integration (통합) Transcrpition (전사) Attachment (부착) Fusion (융합) Reverse transcription (역전사) Integration (통합) Transcrpition (전사) Translation (유전자암호 해독) Viral assembly (조립) Budding and Maturation of HIV virion (HIV virion의 돌출과 성숙) capsid Retrovirus는 lipid envelope에 의해 둘러싸여 있는 protein capsid안에 packaged된 RNA genome을 가지는 infectious particle이다. lipid envelope은 infection 과정 초기에 host cell의 membrane receptor와 결합할 수 있는 receptor binding protein을 포함하는 polypeptide chain을 가진다. Retrovirus는 유전물질로서 DNA 대신 RNA와 DNA를 만드는 reverse transcriptase을 가지고 있다. Retrovirus가 cell에 감염되면, cytoplasm으로 reverse transcriptase와 RNA를 주입된다. 그 후, chromosomal DNA를 생성하고 host DNA에 삽입되어 복제를 시작한다 JAMA. 2002;287(13):1635-1637

HIV Life Cycle and Anti-HIV Drug Design Nucleoside reverse transcriptase inhibitors (NRTIs) Nucleotide reverse transcriptase inhibitors (NtRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Fusion inhibitors (FIs) co-receptor inhibitors (CRIs) Integrase inhibitors (INIs)

Mechanism of action AZV Aciclovir differs from previous nucleoside analogues in containing only a partial nucleoside structure : the sugar ring is replaced with an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (acyclo-GTP), by cellular kinases. Acyclo-GTP has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GTP is incorporated into viral DNA, resulting in premature chain termination. Although aciclovir resembles a nucleotide, it has no 3' end. Therefore, after its incorporation into a growing DNA strand, no further nucleotides can be added to this strand. It has also been shown that viral enzymes cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases. In sum, aciclovir can be considered a prodrug: it is administered in an inactive (or less active) form and is metabolised into a more active species after administration.

Mechanism of action of the NRTIs Cytosine(C) Deoxycytidine type

NRTIs currently undergoing either phase II or phase III of clinical trials. Cytosine(C) racivir apricitabine Adenine(A) amdoxovir elvucitabine

Structures of NtRTIs.

Structures of anti-HIV NNRTIs. etravirine delavirdine nevirapine FDA-approved Phase II or III 특징 : 저항성(resistance)이 빠르다. 다른 항레트로바이러스 약물과 병용 투여하도록 승인 화학변화 없이 직접억제

Structures of anti-HIV PIs. saquinavi ritonavir darunavir indinavir tipranavir fosamprenavir nelfinavi atazanavir amprenavir lopinavir/ritronavir FDA-approved