Peptidomimetic inhibitors of HIV-1 protease

In recent years a number of potent peptidomimetic inhibitors of HIV-1 protease have been reported in the literature. One highly potent series was designed to be symmetric molecules to complement the enzyme [60] (Fig. 10). However, as with renin inhibitors, these analogs often carry with them the properties associated with peptides low cellular activity and poor oral bioavailability. The quest, therefore, for a nonpeptide inhibitor again became the focus of our efforts as well as that of numerous other laboratories. In contrast to the renin studies. 

Exploring the available conformational space within a reasonable amount of time is often very difficult for a molecule with many rotatable bonds (e.g., peptidomimetic inhibitors of HIV-1 protease). Therefore, the results are sensitive to the length of the simulation. 

Frecer, V., Berti, F., Benedetti, F., Miertus, S. Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing -Phe Psi Pro- core and displaying favourable ADME-related properties. J. Mol. Graph. Model. 2008, 27, 376-87. 

CGP 57813 is a peptidomimetic inhibitor of human HIV-1 protease. This lipophilic compound has been successfully entrapped in polylactic acid (PLA) and into pH-sensitive methacrylic acid copolymer particles (EUDRAGIT L 1 GO-55) [69], After the application of a film-coating, the plasma concentration was acceptable and reached similar levels as with injections of drug-loaded PLA carriers. To hinder the proteolytic degradation of a drug, two types of enteric-coated pellets were applied simultaneously. One contained the protease inhibitor coated... 

Indinavir is a peptidomimetic hydroxyethylene HIV protease inhibitor. It is formulated as the sulfate salt to yield better solubility and more consistent plasma concentrations as compared with the free base. The molecule was based on a renin inhibitor with some similarity to a phenylalanine-proline cleavage site in the HIV polyprotein, although indinavir is not itself a renin inhibitor. Indinavir is tenfold times more potent against the HIV-1 protease than that of HIV-2, and its 95% inhibitory concentration (IC95) for wild-type HIV-1 ranges from 25 to 100 iiM. 

Ritonavir is an inhibitor of the human immunodeficiency virus (HIV) protease which, in combination with nucleoside analogs (600 mg/b.i.d. p.o.), is indicated in the treatment of HIV infection. Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor, which leads to production of noninfectious immature HIV particles. 

Indinavir Indinavir is a peptidomimetic HIV protease inhibitor that is tenfold more potent against the HIV-1 protease than that of HIV-2. Indinavir is absorbed rapidly after oral administration. Unlike other protease inhibitors, food adversely affects indinavir bioavailabitity this can be alleviated by coadministration of ritonavir. Unique adverse effects of indinavir are crystaUuria and nephrolithiasis, which stem from its poor solubility patients should drink at least 2 L of water daily... 

Tipranavir The FDA recently granted approval for tipranavir, the first member of a new class of nonpeptide inhibitors of the HlV-1 protease, in combination therapy. Although it also binds to the active site of the HlV-1 protease, tipranavir differs in structure from previously available peptidomimetic protease inhibitors and retains activity against HIV-1 isolates that are resistant to other HIV protease inhibitors. Tipranavir, coadministered with ritonavir, is approved for the treatment of HIV-1-infected adults with evidence of viral replication and who have received multiple treatment regimens or have HlV-1 strains resistant to multiple protease inhibitors. As noted in a black box ... 

Atazanavir is an antiretroviral agent approved for use in combination with other antiretroviral agents for the treatment of HIV infections. Atazanavir is a peptidomimetic transition-state inhibitor that targets HIV-1 protease and reduces the viral replication and, thus, the virulence of HIV-1. Similar to saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir, the drug is used in combination with RT inhibitors to produce excellent efficacy in patients with AIDS. 

In the second example, in which desolvation influences were considered, Reddy et al. used a computer-assisted ligand design method that combines molecular mechanics, molecular dynamics, FEP calculations, synthesis, and biochemical testing of peptidomimetic inhibitors, plus crystallographic structure determination of the protein-inhibitor complexes. This combination of techniques successfully led to the design of novel inhibitors for the HIV-1 protease enzyme. This study involved a large set of molecules whose relative binding affinities, predicted via the FEP method prior to synthesis, were later confirmed by experimental measurements. 

Indinavir is a peptidomimetic hydroxy ethylene protease inhibitor that is ten times more potent against HIV-1 enzyme than HIV-2. Following the binding of indinavir to the viral protease, the protease is no longer able to process the gag-pol polyprotein precursors, resulting in the production of immature HIV particles that lack the... 

Finally, Samuelsson and co-workers designed a new C2-symmetric HIV-PR inhibitor, on the basis of X-ray crystal structures, which indicated that the HIV protease existed as a C2-symmetric dimer. The peptidomimetic scaffold of this new class of inhibitors was based on D-mannitol and duplication of the C-terminus. Compounds 21 and 22 were rapidly synthesized and displayed comparable enzyme-inhibitory and antiviral potencies to Indinavir (Figure 24.4, Table 24.1).29-32... 

Lopinavir is a peptidomimetic HIV protease inhibitor that is structurally similar to ritonavir but is three- to tenfold more potent against HIV-1 in vitro. Lopinavir is active against both HIV-1 and HIV-2 its IC50 for wild-type HIV variants in the presence of 50% human serum ranges from 65 to 290 nM. Lopinavir is available only in coformulation with low doses of ritonavir, which is used to inhibit CYP3A4 metabolism and increase concentrations of lopinavir. 

Ritonavir is a peptidomimetic HIV protease inhibitor designed to complement the C2- symmetry of the enzyme active site. Ritonavir is active against both HIV-1 and HIV-2, althongh it may be slightly less active against the latter. Its IC50 for wild-type HIV-1 variants in the absence of hnman sernm ranges from 4 to 150 nM. 

Saquinavir is a peptidomimetic hydroxyethylamine HIV protease inhibitor. It is a transition-state analog of a phenylalanine-proline cleavage site in one of the native substrate sequences for the HIV aspartyl protease and was the product of a rational drug-design program. Saquinavir inhibits both HIV-1 and HIV-2 replication and has an in vitro IC50 in peripheral blood lymphocytes that ranges from 3.5 to 10 nM. 

Saquinavir Saquinavir is a peptidomimetic HIV protease inhibitor that inhibits HIV-1 and HIV-2 replication. Of aU of the HIV protease inhibitors, saquinavir inhibits CYP3 A4 least potently. Typically, saquinavir is administered once or twice daily in combination with ritonavir to improve pharmacokinetics. 

Ritonavir Ritonavir is a peptidomimetic HIV protease inhibitor that is active against HIV-1 and HIV-2. Ritonavir is an extremely potent inhibitor of CYP3A4 and is frequently combined with most of the protease inhibitors to enhance their pharmacokinetic profiles and allow a reduction in dose and dosing frequency. Typically, a low dose of ritonavir (100 or 200 mg twice daily) is used, as it is better tolerated and just as effective at inhibiting CYP3 A4. 

Atazanavir 11 (Figure 16.4A) is an acyclic aza-peptidomimetic, a potent HIV protease inhibitor [43,44] approved recently by the U.S. Food and Drug Adminstration for treatment of autoimmune diseases (e.g., AIDS). An enzymatic process has been developed for the preparation of (lS,2/ )-[3-chloro-2-hydroxy-l-(phenylmethyl)pro-pyljcarbamic acid, 1,1-dimethylethyl ester 13 (Figure 16.4B), akey chiral intermediate... 

A large number of reported peptidomimetic compounds possess very low aqueous solubility at physiological pH owing to the high lipophilicity inherent in these structures. Phosphorylation can yield improved biological activities for such compounds. This is at least the case for the phosphorylated neurokinin-1 receptor antagonist and the HIV protease inhibitor of Fig. 36.7 described by scientists from Merck and Upjohn, respectively. Clean phosphorylation methods are now available some of them are shown in Fig. 36.8. 

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