Agents acting on HIV Protease enzyme

Agents acting on HIV Protease enzyme

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  Agents acting onHIV Protease  Submitted by:- Lakshay Gupta  Submitted to:- Dr. Om Silakari
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  Contents 1. HIV 2. HIVProtease 3. Structure of HIV Protease 4. Drug receptor interactions 5. History of drugs 6. Drugs
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  HIV  The humanimmunodeficiency virus (HIV) is a retrovirus belonging to the family of lentiviruses. Retroviruses can use their RNA and host DNA to make viral DNA and are known for their long incubation periods. Like other retroviruses, HIV infects the body, has a long incubation period (clinical latency), and ultimately causes the signs and symptoms of disease, here AIDS. HIV causes severe damage to the immune system and eventually destroys it by using the DNA of CD4+ cells to replicate itself. In that process, the virus eventually destroys the CD4+ cells.
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  HIV Protease  HIV-Pis a symmetrical homodimer of identical 99 residue monomers, structurally and mechanistically similar to the pseudosymmetric pepsin family of proteases, whose members include renin.  The aspartyl endoprotease encoded by human immunodeficiency virus catalyses essential events in the maturation of infective virus particles.
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  Structure  The activesite of the enzyme is C2 symmetric in the absence of substrates or inhibitors and contains two essential aspartic acid residues (Asp25 and Asp25’). The entrance to the active site is partly occluded by ‘flaps’ constructed by 2 beta strands from each monomer, connected by a turn. In the absence of substrate, the flaps are flexible.
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  Drug-Receptor Interactions  Uponbinding of inhibitors, the residues within the flaps undergo movements upto several angstroms to interact with the bound ligand.  A single tightly bound water is observed in the structures of most HIV-P-inhibitor complexes, accepting hydrogen bonds from the backbone amides of both flap residues and donating to carbonyls of the bound inhibitors. This is referred to as the ‘flap’ water. Despite the presence of this water and several tightly bound water molecules on the floor of the active site, the cavity also contains extensive hydrophobic surface area.
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   Subnanomolar inhibitor(modified octapeptide) was used to define the extensive hydrophobic and hydrogen bonding interactions available in the HIV-P active site.  The central hydroxy group of inhibitors interact with the carboxylates of both Asp25 and Asp25’. This hydroxyl group replaces a water molecule that likely binds between these aspartyl side chains during peptide hydrolysis by HIV-P.
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  History of drugs Alcohol diamines and diol diamines were examined and entered clinical trials as antiviral agent for intravenous treatment of AIDS.  The X-ray structure of complexes between HIV-P and diol diamine derivatives showed that although one of the hydroxyl groups bound between the catalytic aspartyl carboxylates and made contacts with both, the second hydroxyl made only one such contact. Thus the cost of desolvating the second inhibitor hydroxyl upon binding is not compensated by strongly favorable interactions in the complex.
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   A seriesof cyclic ureas were designed to interact with both the aspartyl carboxylates and the Ile50 and Ile50’ backbone amides that hydrogen bond with the flapwater. The compounds interacted with the HIV-P in a highly symmetrical fashion as they had been designed to do so, with the urea replacing the flap water.  This compound showed animal toxicity and thus wasn’t processed further.
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  Drugs
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  Saquinavir  It wasthe first HIV-P inhibitor approved for human use.  Precursor of Saquinavir comprises of proline at one site and phenylalanine at the other.
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  Indinavir  Indinavir wasthe result of successful application of SBDD at Merck to overcome the problem of low bioavailability due to low solubility.  Crixivan ( the sulphate of Indinavir) was successfully launched for use as an antiviral drug.
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  Amprenavir  Amprenavir isthe most recent addition to the HIV-P inhibitors approved for human antiviral treatment.  It was designed to minimize molecular weight to increase oral bioavailability.
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  Thank You