Discovery and development of HIV-protease inhibitors
Many major physiological processes depend on regulation of
History
Human immunodeficiency virus (HIV) is a lentivirus that has two major species, HIV-1 which causes the majority of the epidemic, and HIV-2, a close relative whose distribution is concentrated in western Africa.[6] HIV infection was first described in 1981 in San Francisco and New York City.[7] In 1985, HIV was identified as the causative agent of acquired immune deficiency syndrome (AIDS) and its complete genome was immediately available. This knowledge paved the way for the development of selective inhibitors.[6]
HIV-2 carries a slightly lower risk of transmission than HIV-1 and infection tends to progress more slowly to AIDS.[7] In common usage HIV usually implies HIV-1.[8]
HIV-1 protease is one of the best known
After the discovery of HIV protease it only took 10 years for its first inhibitor to reach the market.[10] The first reports of highly selective antagonists against the HIV protease were revealed in 1987. Phase I trials of saquinavir began in 1989 and it was the first HIV protease inhibitor to be approved for prescription use in 1995. Four months later, two other protease inhibitors, ritonavir and indinavir, were approved.[6] In 2009, ten protease inhibitors have reached the market for treatment against HIV but one protease inhibitor, amprenavir, was withdrawn from the market in 2004.[6][11]
Life cycle of HIV
HIV belongs to the class of viruses called
Mechanism of action
There are several steps in the HIV life cycle that may be interfered with, thus stopping the replication of the virus. A very critical step is the proteolytic cleavage of the polypeptide precursors into mature enzymes and structural proteins catalyzed by HIV protease.[12] HIV protease inhibitors are peptide-like chemicals that competitively inhibit the action of the virus aspartyl protease. These drugs prevent proteolytic cleavage of HIV Gag and Pol polyproteins that include essential structural and enzymatic components of the virus. This prevents the conversion of HIV particles into their mature infectious form.[6]
Protease inhibitors can alter
Design
Protease inhibitors were designed to mimic the
Binding site
The HIV protease is a C2-symmetric homodimeric enzyme consisting of two 99
HIV proteases catalyze the hydrolysis of peptide bonds with high sequence selectivity and catalytic proficiency. The mechanism of the HIV protease shares many features with the rest of the aspartic protease family although the full detailed mechanism of this enzyme is not fully understood.[12] The water molecule seems to play a role in the opening and closing of the flaps as well as increasing the affinity between enzyme and substrate. The aspartyl residues are involved in the hydrolysis of the peptide bonds.[17] The preferred cleavage site for this enzyme is the N-terminal side of proline residues, especially between phenylalanine and proline or tyrosine and proline.[6][16]
Development
The first HIV protease inhibitor, saquinavir, is a peptidomimetic hydroxyethylamine[6] and was marketed in 1995.[18] It is a transition state analogue of a native substrate of the protease.[6] The observation that HIV-1 protease cleaves the sequences containing the dipeptides Tyr-Pro or Phe-Pro was the basic design criterion.[19] Addition of the decahydroisoquinoline (DIQ) group was one of the most significant modifications that led to the discovery of saquinavir. This substituent improves aqueous solubility and potency by limiting the conformational freedom of the inhibitor.[20] Saquinavir is effective against both HIV-1 and HIV-2[5] and is usually well tolerated but high serum concentration is not achieved.[11]
Ritonavir, a peptidomimetic HIV protease inhibitor, was marketed in 1996.[18] It was designed to fit the C2-symmetry in the binding site of the protease.[6] The developers of ritonavir, Abbott Laboratories, started with compounds that were active against the virus but had poor bioavailability. Some improvements were made, for example the terminal phenyl residues were removed and pyridyl groups put instead to add water solubility. The final product of these improvements was ritonavir.[19] Significant gastrointestinal side effects and a large pill burden are ritonavir's main drawbacks and is therefore not used as a single treatment.[11] However, it is a strong inhibitor of the cytochrome P450 enzyme mediated metabolism[19] and it is only used in a combination therapy with other protease inhibitors for pharmacokinetic boosting.[11]
Indinavir, which is a peptidomimetic hydroxyethylene HIV protease inhibitor, reached the market in 1996.[6][18] The design of indinavir was guided by molecular modeling and the X-ray crystal structure of the inhibited enzyme complex. The terminal phenyl constituents contribute hydrophobic binding to increase potency.[19] It is an analogue of the phenylalanine-proline cleavage site of the HIV Gag-polyprotein.[6]
Amprenavir reached the market in 1999.
Lopinavir was marketed in 2000[18] and was originally designed to diminish the interactions of the inhibitor with Val82 of the HIV-1 protease, a residue that is often mutated in the drug resistant strains of the virus.[19] It is a peptidomimetic HIV protease inhibitor[6] and its core is identical to that of ritonavir. Instead of the 5-thiazolyl end group in ritonavir, lopinavir has a phenoxyacetyl group and the 2-isopropylthiazolyl group in ritonavir was replaced by a modified valine in which the amino terminal had a six-membered cyclic urea attached.[19]
Fosamprenavir was marketed in 2003[18] and is a phosphoester prodrug that is rapidly and extensively metabolized to amprenavir.[21] The solubility and bioavailability is better than of amprenavir[6] which results in reduced daily pill burden.[22]
Tipranavir is a nonpeptidic HIV-1 protease inhibitor[11] and reached the market in 2005.[18] Unlike other HIV protease inhibitors on the market, tipranavir was developed from a nonpeptidic coumarin template and its antiprotease activity was discovered by high-throughput screening.[23] This sulfonamide containing 5,6-dihydro-4-hydroxy-2-pyrone had emerged from screenings of 3-substituted coumarins and dihydropyrones.[24] It possesses broad antiviral activity against multiple protease inhibitor resistant HIV-1.[25]
Darunavir reached the market in 2006[18] and is a nonpeptidic analogue of amprenavir, with a critical change at the terminal tetrahydrofuran (THF) group. Instead of a single THF group, darunavir contains two THF groups fused in the compound, to form a bis-THF moiety which makes it more effective than amprenavir. With this structural change, the stereochemistry around the bis-THF moiety confers orientational changes, that allows for continued binding with the protease which has developed a resistance for amprenavir.[26]
All the FDA approved protease inhibitors are listed below.
Saquinavir | Nelfinavir | Ritonavir | Lopinavir |
Amprenavir | Fosamprenavir | Darunavir | |
Indinavir | Atazanavir | Tipranavir |
Structure-activity relationship
All the HIV protease inhibitors on the market contain a central core motif consisting of a hydroxyethylen scaffold, with the only exception being the central core of tipranavir, which is based on a coumarin scaffold.
Resistance
Mutations that code for alterations of the conformational shape facilitate resistance of HIV to protease inhibitors.[26] The locations of these mutations are primarily in the active site of the HIV protease enzyme as well as outside of the active site, including those at protease cleavage sites in the Gag-Pol polyprotein precursors. The cleavage sites have highly diverse sequences, so the protease recognizes its substrates not based on sequence but rather the conserved 3D shape the substrates share when bound at the active site. This conserved shape has been named the substrate envelope.[30] The active site mutations have been shown to directly change the interactions of the inhibitors, and mostly occur at positions where inhibitors contact protease residues beyond the substrate envelope.[31] The non-active site mutations are considered to affect by other mechanisms, like influencing dimer stability and conformational flexibility.[32][33]
Over 100 single gene
The Stanford HIV RT and Protease Sequence Database (also called the “HIV Drug Resistance Database”) was formed in 1998 with HIV reverse transcriptase and protease sequences from persons with well-characterized antiretroviral treatment histories, and is publicly available to query resistance mutations and genotype-treatment, genotype-phenotype, and genotype-outcome correlations[citation needed]
Although the substrate envelope provides the general strategy of designing inhibitors that mimic the substrate and stay within the envelope to avoid resistance conferred by most active site mutations,[36][37] there is no general strategy to tackle the problem of drug resistance, especially due to those away from the active site. Researches directed towards development of new therapies to cure AIDS are focused on avoiding cross-resistance to drugs that are already on the market.[12]
Current status
In January 2018 darunavir was still the most recent HIV protease inhibitor to reach the market.[38]
In 2006,
In the summer of 2009, GlaxoSmithKline and Concert Pharmaceuticals announced their collaboration to develop and commercialise deuterium-containing medicines. One of them is CTP-518, a protease inhibitor for the treatment of HIV, expected to enter phase I clinical trials in the second half of 2009. CTP-518 is a novel HIV protease inhibitor developed by replacing certain key hydrogen atoms of atazanavir with deuterium. Pre-clinical studies have demonstrated that this modification fully retains the antiviral potency but can evidently slow hepatic metabolism and thereby increase the half life and plasma trough levels. CTP-518, therefore, has the potential to be the first HIV protease inhibitor to eliminate the need to co-dose with a boosting agent, such as ritonavir.[40]
See also
- Antiretroviral drug
- Reverse transcriptase inhibitor
- Integrase inhibitor
- Entry inhibitor
- Discovery and development of non-nucleoside reverse transcriptase inhibitors
- Discovery and development of NS5A inhibitors
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