The viral enzyme HIV-1 protease, or HIV-1 PR, plays an essential role in HIV replication by cutting newly synthesized HIV proteins at highly specific regions, yielding mature proteins that are subsequently assembled into a functional virus. The important role this molecule plays in viral replication makes it a key HIV drug target, according to Centers for Disease Control and Prevention.
Structure
Investigations into the molecular structure of HIV-1 PR have been carried out using the techniques such as X-ray crystallography, in which short wavelengths of light are bounced off the protein to determine the exact position of each atom. These studies showed HIV-1 PR to be composed of two identical subunits, each made up of 99 amino acids, the molecular building blocks of proteins, according to an April 2007 article published in "Proteins."
Aspartate Protease
The mechanism HIV-1 PR uses to cut newly synthesized viral proteins is dependent upon two key aspartate amino acids present in the functional site of this molecule. HIV-1 PR is a member of an enzyme family called aspartate proteases, which all function through a similar mechanism. These enzymes use a water molecule to split viral protein chains and function most effectively in acidic conditions, according to a February 2008 article published in "Current Opinion in Structural Biology."
Mechanism
The two subunits of HIV-1 PR come together forming a tunnel, into which newly synthesized HIV proteins fit. HIV-1 PR has two flexible domains thought to operate as flaps that escort HIV proteins into the tunnel, after which the enzyme changes its structure, facilitating cutting of HIV proteins, according to a January 2003 article published in "Organic Biomolecular Chemistry."
Drug Therapy
Numerous drugs have been designed to reduce HIV viral replication by targeting of HIV-1 PR. Inhibitors of HIV-1 PR have been developed to mimic the structure of the amino acid chain regions this enzyme recognizes in order to bind to the enzymes functional site, thereby blocking its activity and reducing the progression of HIV, according to a January 2009 article published in "Handbook of Experimental Pharmacology."
HIV-1 PR Mutation
Like other retroviruses, HIV mutates extremely rapidly, developing resistance to previously successful drugs incredibly quickly, providing a difficult challenge for the HIV research community. HIV-1 PR is particularly problematic, as even small mutations in the functional part of this enzyme may result in failure of a drug molecule to bind to HIV-1 PR according to March 2000 paper published in "Biochemica et Biophysica acta."
References
- "Organic Biomolecular Chemistry"; HIV-1 Protease: Mechanism and Drug Discovery; A. Brik, C. Wong; January 2003
- "Proteins"; Atomic Resolution Crystal Structures of HIV-1 Protease and Mutants V82A and I84V with Saquinavir; Y. Tie; April 2007
- "Current Opinion in Structural Biology"; HIV-1 protease folding and the design of drugs which do not create resistance; R. Broglia; February 2008
- "Handbook of Experimental Pharmacology"; Viral Protease Inhibitors; J. Anderson et al.; February 2008
