Acyclovir

2013.03.15Lee, sang-hwi

1) Attachment ( 부착 )2) Fusion ( 융합 )3) Reverse transcription ( 역전사 )4) Integration ( 통합 )5) Transcrpition ( 전사 )6) Translation ( 유전자암호 해독 )7) Viral assembly ( 조립 ) 8) Budding and Maturation of HIV virion (HIV virion 의 돌출과 성숙 )• Retrovirus 는 lipid envelope 에 의해 둘러싸여 있는 protein capsid 안에 packaged 된 RNA genome 을 가지는 infectious particle 이다 . • lipid envelope 은 infection 과정 초기에 host cell의 membrane receptor 와 결합할 수 있는 receptor binding protein 을 포함하는 polypeptide chain 을 가진다 . • Retrovirus 는 유전물질로서 DNA 대신 RNA 와 DNA를 만드는 reverse transcriptase 을 가지고 있다 .

• Retrovirus 가 cell 에 감염되면 , cytoplasm 으로 re-verse transcriptase 와 RNA 를 주입된다 .

• 그 후 , chromosomal DNA 를 생성하고 host DNA에 삽입되어 복제를 시작한다

capsid

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 NRTIsCytosine(C)

Deoxycytidine type

NRTIs currently undergoing either phase II or phase IIIof clinical trials.

apricitabine racivir

amdoxovir elvucitabine

Cytosine(C)

Adenine(A)

Structures of NtRTIs.

Structures of anti-HIV NNRTIs.

FDA-approved Phase II or III

etravirine

nevirapinedelavirdine

특징 : 저항성 (resistance) 이 빠르다 . 다른 항레트로바이러스 약물과 병용 투여하도록 승인 화학변화 없이 직접억제

Structures of anti-HIV PIs.

FDA-approved

saquinavi

ritonavir

darunavirindinavir

tipranavirfosamprenavir

nelfinavi

atazanavir

lopinavir/ritronaviramprenavir