Crixivan
Human Immunodeficiency Virus protease inhibitorHuman Immunodeficiency Virus protease inhibitor
<StructureSection load='2b7z' size='340' side='right' caption='Crixivan molecule and structure of HIV-1 protease bound to Crixivan, (2b7z), resolution 2.20Å' scene='74/745991/Crixivan/2'>
StructureStructure
Crixivan, also known as Indinavir, is an antiviral compound that acts as a protease inhibitor. The has a molecular weight of 711.875 g/mol and is very soluble in water and ethanol.[1] Crixivan works by specifically binding to the HIV-1 protease active site by mimicking a target substrate protein and essentially becoming “stuck” in the enzyme active site, disabling the enzyme. The pyridine ring on Crixivan conforms the molecule to the active site. The hydroxyethylene group stabilizes the molecule and prevents cleavage.
FunctionFunction
Crixivan functions as a competitive inhibitor affecting the HIV-1 protease protein. Crixivan mimics the target substrate of the HIV protease and binds to the protease active site. The HIV protease enzyme is essential for the reproduction of the HIV virus and further infection. HIV protease performs post-translational cleavage of multi-protein peptides, such as the Gag protein, that serve as important factors in virus development. HIV protease is released from the viral particle soon after the cell is infected and immediately begins cleaving the multi-protein peptides into vital proteins such as reverse transcriptase, integrase, and protease. The virus will halt development if the polypeptides are not cleaved and the resulting particles from the virus will be non-infective. The hydrophobic phenyl functional groups located on the terminal ends of Crixivan increase the potency of the drug compared to earlier protease inhibitors.[2]
MechanismMechanism
The of HIV-1 protease is inhibited by Crixivan when the molecule interacts with the specific sites that a Gag protein peptide would normally interact with. The active site contains Asp25, which is involved in peptide cleavage, Thr26, which is involved in stabilizing the active site conformation, and Gly27, which is involved in the binding of a protein in a position that gives Asp25 access to its cleavage site.[3] Arg8 also plays a role in holding a substrate in place in the enzyme active site. When the Crixivan molecule enters the protease active site it imitates the transition state of Gag protein peptides during the cleavage reaction. The virus' peptide bonds [-NH-CO-] can be cleaved via aspartic catalysis[1]. Crixivan contains a hydroxyethylene [-CH2-CH(OH)-] site instead that cannot be cleaved by Asp25.[4] The molecule becomes stuck inside the active site because of the hydrogen bonds between Arg8 and Crixivan's pyridine ring and the interactions between Gly27 and Crixivan's aromatic rings.[5] This blocks all further cleavage of viral peptides by the protease molecule.
Cellular EffectsCellular Effects
Crixivan blocks the cleavage of the Gag multi-protein peptide. This inhibition does not allow for the maturation of new viral particles produced from infected cells. Viral particles that do not mature will not be able to infect new cells, lowering the viral load. Protease inhibitors do not have any effect on already infected cells but they do prevent further cell-to-cell transmission of the virus.[2]
ReferencesReferences
- ↑ Physicians Desk Reference 66th ed. PDR Network, LLC, Montvale, NJ. p. 2086 (2012)
- ↑ 2.0 2.1 Scholar, E. M., & Pratt, W.B. (2000). The Antimicrobial Drugs (2nd ed.). New York, NY: Oxford University Press.
- ↑ Mager PP. The active site of HIV-1 protease. Med Res Rev. 2001 Jul;21(4):348-53. PMID:11410934
- ↑ De Clercq E. The history of antiretrovirals: key discoveries over the past 25 years. Rev Med Virol. 2009 Sep;19(5):287-99. doi: 10.1002/rmv.624. PMID:19714702 doi:http://dx.doi.org/10.1002/rmv.624
- ↑ Mahalingam B, Wang YF, Boross PI, Tozser J, Louis JM, Harrison RW, Weber IT. Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site. Eur J Biochem. 2004 Apr;271(8):1516-24. PMID:15066177 doi:10.1111/j.1432-1033.2004.04060.x