Drugs for AIDS/HIV
May 10, 2009 – 7:05 am
AIDS caused by the replication of the human immunodeficiency virus (HIV). It is susceptible to targeted interventions, because several virus specific metabolic steps occur in infected cells (A). Viral RNA must first be transcribed into DNA, a step catalyzed by viral “reverse transcriptase.” Doublestranded DNA is incorporated into the host genome with the help of viral integrase. Under control by viral DNA, viral replication can then be initiated, with synthesis of viral RNA and proteins (including enzymes such as reverse transcriptase and integrase, and structural proteins such as the matrix protein lining the inside of the viral envelope). These proteins are assembled not individually but in the form of polyproteins. These precursor proteins carry an N-terminal fatty acid (myristoyl) residue that promotes their attachment to the interior face of the plasmalemma. As the virus particle buds off the host cell, it carries with it the affected membrane area as its envelope. During this process, a protease contained within the polyprotein cleaves the latter into individual, functionally active proteins.
I. Inhibitors of Reverse Transcriptase
IA. Nucleoside agents
Nucleoside agents are analogues of thymine (azidothymidine, stavudine), adenine (didanosine), cytosine (lamivudine, zalcitabine), and guanine (carbovir, a metabolite of abacavir). They have in common an abnormal sugar moiety. Like the natural nucleosides, they undergo triphosphorylation, giving rise to nucleotides that both inhibit reverse transcriptase and cause strand breakage following incorporation into viral DNA.
The nucleoside inhibitors differ in terms of 1) their ability to decrease circulating HIV load; 2) their pharmacokinetic properties (half life—>dosing interval—>compliance; organ distribution—>passage through blood-brainbarrier); 3) the type of resistance-inducing mutations of the viral genome and the rate at which resistance develops; and 4) their adverse effects (bone marrow depression, neuropathy, pancreatitis).
IB. Non-nucleoside inhibitors
The non-nucleoside inhibitors of reverse transcriptase (nevirapine, delavirdine, efavirenz) are not phosphorylated. They bind to the enzyme with high selectivity and thus prevent it from adopting the active conformation. Inhibition is noncompetitive.
II. HIV protease inhibitors
Viral protease cleaves precursor proteins into proteins required for viral replication. The inhibitors of this protease (saquinavir, ritonavir, indinavir, and nelfinavir) represent abnormal proteins that possess high antiviral efficacy and are generally well tolerated in the short term. However, prolonged administration is associated with occasionally severe disturbances of lipid and carbohydrate metabolism. Biotransformation of these drugs involves cytochrome P450 (CYP 3A4) and is therefore subject to interaction with various other drugs inactivated via this route.
For the dual purpose of increasing the effectiveness of antiviral therapy and preventing the development of a therapy-limiting viral resistance, inhibitors of reverse transcriptase are combined with each other and/or with protease inhibitors.
Combination regimens are designed in accordance with substancespecific development of resistance and pharmacokinetic parameters (CNS penetrability, “neuroprotection,” dosing frequency).
source: Lullmann. 2000. Color Atlas of Pharmacology. Thieme
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