HIV-1 protease inhibitors containing a novel C2 symmetrical hydroxyalkylgem-diamino core structure

Two series of peptidomimetics containing a novel C₂ symmetrical hydroxyalkylgem-diamino core structure were prepared, from amino acid starting materials, and evaluated as inhibitors of HIV-1 protease (HIV-1 Pr). 1, 1-Diamino-3-hydroxypropane (gHse) derivatives showed weak inhibitory potency (IC₅₀> 10 μM). In the 1, 1-diamino-2-hydroxyethane (gSer) series, a compound containing P1/P1’benzyl and P2/P2’Fmoc substitueras, displayed a significant HIV-1 Pr inhibition (IC₅₀= 440 nM). © Munksgaard 1997.     

Human immunodeficiency virus type 1 protease inhibitor attenuates Candida albicans virulence properties in vitro.

The putative virulence factor secreted aspartyl proteinase (SAP) of Candida albicans and the human immunodeficiency virus type 1 (HIV-1) protease both belong to the aspartyl proteinase family. The present study demonstrates that the HIV-1 protease inhibitor Indinavir is a weak but specific inhibitor of SAP. In addition, Indinavir reduces the amount of cell bound as well as released SAP antigen from C. albicans. Furthermore, viability and growth of C. albicans are markedly reduced by Indinavir. These findings indicate that HIV-1 protease inhibitors may possess antifungal activity and we speculate that in vivo SAP inhibition may add to the resolution of mucosal candidiasis in HIV-1 infected subjects.     

Conformational studies of irreversible HIV-1 protease inhibitors containing cis-epoxide as an amide isostere

Abstract: We have carried out NMR and molecular modeling studies of peptidomimetic HIV-1 protease inhibitors, LB71116: Qc-Asn-Pheψ[(1R,2S)-cis-epoxide]Gly-NH-CH(isopropyl)₂ where Qc stands for quinaldic acid and LB71148: Qc-(SMe)Pen(O)₂-Pheψ[(1R,2S)-cis-epoxide]Gly-NH-CH(isopropyl)₂ where (SMe)Pen(O)₂ stands for S-methyl-S-dioxo-penicillamine. Through conformational calculations and NMR data analysis, we have obtained preferred conformations of the two inhibitors in solution. To our knowledge, this work is one of the first extensive conformational studies of peptidomimetics containing cis-epoxide amide isostere. The resulting preferred conformations contain extended structures. In these conformations, the ψ of Phe(cep) is maintained about 130° and the φ angle of (cep)Gly prefers ± 150°[where Phe(cep) and (cep)Gly are the residues generated by the replacement of the Phe-Gly peptide bond with cis-epoxide]. Two conformations were commonly observed in the preferred conformations of each inhibitor. Through restrained molecular dynamics simulating the hydrogen bond formation between our inhibitor and a water molecule (‘flap water’), one of the conformations is assumed as the conformation which can bind to the enzyme without large conformational changes. Recently, we had the opportunity to compare the selected preferred conformation with the binding conformation of LB71116 observed from the X-ray studies of the complex between LB71116 and HIV-1 protease. These two conformations are surprisingly similar to each other. Thus, we can explain high activity and selectivity of our inhibitors to the HIV-1 protease by the similarity between the preferred conformations in solution and the binding conformation.     

Development of Activity Assays for High-Volume Evaluation of Human Immunodeficiency Virus (HIV) Protease Inhibitors in Rat Serum: Results with Ditekiren

We showed previously that a commercially available synthetic tetradecapeptide, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser, produces authentic angiotensin I (Ang I) upon incubation with the HIV-1 protease (S. K. Sharma et al., Anal. Biochem. 198:363, 1991). Therefore, we developed an Ang-I based activity assay for HIV protease inhibitors based on the technology developed earlier (M. J. Ruwart et al., Pharm. Res. 7:407, 1990; S. K. Sharma et al., Anal. Biochem. 186:24, 1990) for tracking renin inhibitors in rat sera. Ditekiren was either extracted from sera with ethyl acetate or assayed after the interfering substances in sera were precipitated with acetonitrile. Purified recombinant HIV-1 protease was added to extracted rat serum and the enzymatic reaction was initiated in the presence of the tetradecapeptide substrate. The inhibition of Ang I production was measured by a commercially available RIA kit. The cleanup methodology also enabled a commercially available Proteinase Scintillation Proximity Assay (SPA, Amersham) to quantify ditekiren in rat serum through the addition of recombinant HIV-1 protease and cleavage of substrate from SPA beads. Results were confirmed by HPLC or by the renin assay for ditekiren, which inhibits both aspartyl proteases. These technologies should prove useful for assessing serum levels of HIV protease inhibitors in rat.     

Lopinavir/ritonavir: a protease inhibitor for HIV-1 treatment

Background: Lopinavir is a protease inhibitor with high specificity for HIV-1 protease formulated with ritonavir. Numerous clinical trials have shown that lopinavir/ritonavir (LPV/r) is highly effective as a component of highly active antiretroviral therapy (HAART) regimens for HIV-1 infection. Objective: In this article we provide an overview of the properties of LPV/r and the experience with its use in HIV-infected adults and adolescents. Methods: We reviewed the literature and selected the most important published articles on LPV/r and the latest posters/communications presented in conferences, with particular attention to the clinical efficacy and tolerability of LPV/r in HIV-1 infected patients. Conclusion: LPV/r is highly effective as a component of HAART regimens for HIV-1 infection. There is considerable experience with the drug in both treatment-naive and treatment-experienced patients. In general, LPV/r is well tolerated and its high genetic barrier to resistance favours long-term efficacy.     

Tipranavir: a novel protease inhibitor for HIV therapy

Tipranavir (TPV) is a nonpeptidic protease inhibitor with potent in vitro activity against most HIV-1 strains resistant to other protease inhibitors. In vitro data have shown that resistance to TPV develops slowly. When coadministered with ritonavir (RTV) as a booster, TPV has shown potent antiviral activity in multiple antiretroviral-experienced patients. In the RESIST-1 and RESIST-2 studies, the efficacy and safety of TPV/RTV (500/200 mg twice daily) in highly treatment-experienced HIV-1-positive patients was assessed. Analysis at 48 weeks showed that TPV/RTV-containing regimens significantly improved immune and virological responses compared with a RTV-boosted comparator protease inhibitor plus optimized background regimen. TPV is generally well tolerated; nevertheless, clinical hepatitis and liver decompensation have been associated to its use, together with an indication of an increased risk of intracranial hemorrhage. Extensive listing of drug–drug interactions have been reported with TPV.     

L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.

L-696,474, an inhibitor of the HIV-1 protease, was discovered in extracts of the fungal culture Hypoxylon fragiforme (MF5511; ATCC 20995). L-696,474 is a novel cytochalasin with a molecular weight of 477 and an empirical formula of C30H39NO4. L-696,474 inhibited HIV-1 protease activity with an IC50 of 3 microM and the mode of inhibition was competitive with respect to substrate (apparent Ki = 1 microM). Furthermore, L-696,474 was not a slow-binding inhibitor. The inhibition due to L-696,474 was also independent of the HIV-1 protease concentration. L-696,474 was inactive against pepsin, another aspartyl protease; stromelysin, a zinc-metalloproteinase; papain, a cysteine-specific protease or human leucocyte elastase, a serine-specific protease. Two other novel cytochalasins (L-697,318 and L-696,475) isolated from the same culture were inactive against the HIV-1 protease. Commercially available cytochalasins B, C, D, E, F, H and J were inactive while cytochalasin A was as active as L-696,474 against the HIV-1 protease.     

Possible mechanisms of the antifungal activity of fluconazole in combination with terbinafine against Candida albicans

Context: Candidiasis is a term describing infections by yeasts from the genus Candida, the majority Candida albicans. Treatment of such infections often requires antifungals such as the azoles, but increased use of these drugs has led to selection of yeasts with increased resistance to these drugs.

Objective: Combination therapy would be one of the best strategies for the treatment of candidiasis due to increased resistance to azoles.

Materials and methods: The antifungal activities of fluconazole and terbinafine were evaluated in vitro alone and in combination using broth microdilution test and time kill study. Eventually the expression level of selected genes involved in ergosterol biosynthesis of Candida was evaluated using semi-quantitative RT-PCR.

Results: The obtained results showed the significant MICs ranging from 0.25 to 8?µg/mL followed by FICs ranged from 0.37 to 1 in combination with fluconazole/terbinafine. Our findings have demonstrated that the combination of fluconazole and terbinafine could also significantly reduce the expression of ERG1, 3, and 11 in the cell membrane of Candida in all concentrations tested ranging from 1.73- to 6.99-fold.

Discussion and conclusion: This study was undertaken with the ultimate goal of finding the probable targets of fluconazole/terbinafine in C. albicans by looking at its effects on cell membrane synthesis.     

Transport characteristics of peptides and peptidomimetics: II. Hydroxyethylamine bioisostere‐containing peptidomimetics as substrates for the oligopeptide transporter and P‐glycoprotein in the intestinal mucosa

Abstract: Peptide bond bioisosteres, such as hydroxyethylamine (Hea), have frequently been used to stabilize metabolically labile peptide bonds in peptidomimetic drug design in an effort to increase the oral bioavailability of drug candidates. However, the impact of the peptide bond bioisosteres on the cell permeation characteristics of peptidomimetics is not well understood, particularly with respect to the effects on the substrate activity for proteins that can restrict (e.g. P‐glycoprotein, P‐gp) or facilitate (e.g. the oligopeptide transporter, OPT) intestinal mucosal permeation of peptidomimetics. In this study, terminally free and terminally modified (N‐acetylated and C‐amidated) peptidomimetics of H‐Ala‐Phe‐OH and H‐Ala‐Phe‐Ala‐OH with the Ala‐Phe peptide bonds replaced by Hea bioisosteres were synthesized. Transport characteristics of these peptidomimetics were investigated using Caco‐2 cell monolayers as an in vitro model of the intestinal mucosa. The study showed that the Hea bioisostere stabilized the peptidomimetics to protease metabolism in Caco‐2 cells. All terminally free peptidomimetics showed significant affinity and substrate activity for OPT. The affinity and substrate activity for OPT were stereoselective for peptidomimetics containing an S,S‐configuration for the two adjacent chiral centers related to the Hea bioisostere. Three of the four terminally modified peptidomimetics showed significant substrate activity for P‐gp and, interestingly, the substrate activity for P‐gp was also stereoselective; however, it was in favor of an R,R‐configuration for the two adjacent chiral centers related to the Hea bioisostere.     

Short report: time course of clinical response with fluconazole for Candida oesophagitis in patients with AIDS

Background: Although fluconazole is increasingly utilized for the therapy of Candida oesophagitis in patients with AIDS, the time course of response has not been adequately defined. Methods: Over a 48-month period, all HIV-infected patients undergoing upper endoscopy at a large city-county hospital were identified prospectively. Symptomatic patients with endoscopic and histopathologically confirmed Candida oesophagitis in whom oral antifungal therapy had not been received within the past three months were treated in an open-label fashion with fluconazole 200 mg on the first day followed by 100 mg daily for two weeks. All patients were followed clinically to determine the rapidity of response. Results: Eighteen patients were identified; all but two were male. Candida oesophagitis was graded as severe in 13 patients (72 %). A complete symptomatic response was seen by five days in seven patients (39 %) and by seven days in nine additional patients (cumulative response, 89 %). The two other patients had improved by at least 50% at one week, with a complete symptomatic response seen at two weeks. Conclusions: Our study confirms anecdotal experience suggesting that fluconazole results in a rapid clinical response for Candida oesophagitis in patients with AIDS. Given this rapidity, a one-week course of empiric treatment with fluconazole for HIV-infected patients with newly developed esophageal symptoms could be used as an appropriate time period to assess a response prior to further diagnostic evaluation with endoscopy.     

Fungal biofilm inhibition by piperazine‐sulphonamide linked Schiff bases: Design,synthesis, and biological evaluation

We report the synthesis of some new piperazine‐sulphonamide linked Schiff bases as fungal biofilm inhibitors with antibacterial and antifungal potential. The biofilm inhibition result of Candida albicans proposed that the compounds 6b (IC₅₀ = 32.1 μM) and 6j (IC₅₀ = 31.4 μM) showed higher inhibitory activity than the standard fluconazole (IC₅₀ = 40 μM). Compound 6d (MIC = 26.1 μg/mL) with a chloro group at the para position was found to be the most active antibacterial agent of the series against Bacillus subtilis when compared with the standard ciprofloxacin (MIC = 50 μg/mL). Compound 6j (MIC = 39.6 μg/mL) with an OH? group at the ortho position showed more potent antifungal activity as compared to that of the standard fluconazole (IC₅₀ = 50 μM) against C. albicans. Thus, the synthesized compounds 6a–k were found to be potent biofilm inhibitors as well as active antibacterial and antifungal agents. The molecular docking study of the synthesized compounds against the secreted aspartyl protease (SAP5) enzyme of C. albicans exhibited good binding properties. The in silico ADME properties of the synthesized compounds were also analyzed and showed their potential to be developed as potential oral drug candidates.

     

Quantitative Assessment of HIV-1 Protease Inhibitor Interactions with Drug Efflux Transporters in the Blood–Brain Barrier

Purpose To quantitatively characterize the drug efflux interactions of various HIV-1 protease inhibitors in an in vitro model of the blood–brain barrier (BBB) and to compare that with HIV-1 protease inhibitor stimulated P-glycoprotein (P-gp)-ATPase activity.Methods Cellular accumulation of the P-gp sensitive probe, rhodamine 123 (R123), and the mixed P-gp/multidrug resistance–associated protein (MRP) probe, 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), were evaluated in primary cultured bovine brain microvessel endothelial cells (BBMEC) in the presence of various concentrations of HIV-1 protease inhibitors. The potency (IC₅₀) and efficacy (I_max) of the drugs in the cell accumulation assays for P-gp and/or MRP was determined and compared to activity in a P-gp ATPase assay.Results For R123 (P-gp probe), the rank order potency for inhibiting R123 accumulation in the BBMEC was saquinavir = nelfinavir > ritonavir = amprenavir > indinavir. This correlated well with the rank order affinity in the P-gp ATPase assay. The rank order potency for MRP-related drug efflux transporters, was nelfinavir > ritonavir > saquinavir > amprenavir > indinavir.Conclusions HIV-1 protease inhibitors potently interact with both P-gp and MRP-related transporters in BBMEC. Characterization of the interactions between the HIV-1 protease inhibitors and drug efflux transporters in brain microvessel endothelial cells will provide insight into potential drug–drug interactions and permeability issues in the BBB.     

Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use

Over the past 10 years, protease inhibitors have been a key component in antiretroviral therapies for HIV/AIDS. While the vast majority of HIV/AIDS cases in the world are due to HIV-1, HIV-2 infection must also be addressed. HIV-2 is endemic to Western Africa, and has also appeared in European countries such as Portugal, Spain, and Estonia. Current protease inhibitors have not been optimized for treatment of HIV-2 infection; therefore, it is important to assess the effectiveness of currently FDA-approved protease inhibitors against the HIV-2 protease, which shares only 50% sequence identity with the HIV-1 protease. Kinetic inhibition assays were performed to measure the inhibition constants (K(i)) of the HIV-1 protease inhibitors indinavir, nelfinavir, saquinavir, ritonavir, amprenavir, lopinavir, atazanavir, tipranavir, and darunavir against the HIV-2 protease. Lopinavir, saquinavir, tipranavir, and darunavir exhibit the highest potency with K(i) values of 0.7, 0.6, 0.45, and 0.17 nm, respectively. These K(i) values are 84, 2, 24, and 17 times weaker than the corresponding values against the HIV-1 protease. In general, inhibitors show K(i) ratios ranging between 2 and 80 for the HIV-2 and HIV-1 proteases. The relative drop in potency is proportional to the affinity of the inhibitor against the HIV-1 protease and is related to specific structural characteristics of the inhibitors. In particular, the potency drop is high when the maximum cap size of the inhibitors consists of very few atoms. Caps are groups located at the periphery of the molecule that are added to core structures to increase the specificity of the inhibitor to its target. The caps positioned on the HIV-1 protease inhibitors affect selectivity through interactions with distinct regions of the binding pocket. The flexibility and adaptability imparted by the higher number of rotatable bonds in large caps enables an inhibitor to accommodate changes in binding pocket geometry between HIV-1 and HIV-2 protease.     

Design,Biologic Evaluation,and SAR of Novel Pseudo-peptide Incorporating Benzheterocycles as HIV-1 Protease Inhibitors

A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P₂ ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH₂- of P₁-P₂ linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P₁′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC₅₀ value of 5 nm , also exhibited good anti-SIV activity (EC₅₀ = 0.8 μm ) with low toxicity (TC₅₀ > 100 μm ). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.     

A Comparison of the Bioconversion Rates and the Caco-2 Cell Permeation Characteristics of Coumarin-Based Cyclic Prodrugs and Methylester-Based Linear Prodrugs of RGD Peptidomimetics

Purpose. To compare the bioconversion rates in various biological media and the Caco-2 cell permeation characteristics of coumarin-based cyclic prodrugs (3a, 3b) and methylester-based linear prodrugs (1b, 2b) of two RGD peptidomimetics (la, 2a). Methods. Bioconversion rates of the prodrugs to the RGD peptidomimetics were determined in Hank balanced salt solution (HBSS), pH 7.4, at 37°C and in various biological media (human blood plasma, rat liver homogenate, Caco-2 cell homogenate) known to have esterase activity. Transport rates of the prodrugs and the RGD peptidomimetics were determined using Caco-2 cell monolayers, an in vitrocell culture model of the intestinal mucosa. Results. In HBSS, pH 7.4, the coumarin-based cyclic prodrugs 3a and 3b degraded slowly and quantitatively to the RGD peptidomimetics la and 2a, respectively (3a, t_1/2= 630 ± 14 min; 3b, t_1/2= 301 ± 12 min). The methylester-based linear prodrugs 1b and 2b were more stable to chemical hydrolysis (1b and 2b, t_1/2> 2000 min). Both the coumarin-based cyclic prodrugs and the methylester-based linear prodrugs degraded more rapidly in biological media containing esterase activity (e.g., 90% human blood plasma: 1b, t_1/2< 5 min; 2b, t_1/2< 5 min; 3a, t_1/2< 91 ± 1 min; 3b, t_1/2< 57 ± 2 min). When the apical (AP)-to-basolateral (BL) permeation characteristics were determined using Caco-2 cell monolayers, it was found that the methylester pro-drugs Ib and 2b underwent esterase bioconversion (>80%) to the RGD peptidomimetics 1a and 2a, respectively. In contrast, the cyclic prodrugs 3a and 3b permeated the cell monolayers intact. Considering the appearance of both the prodrug and the RGD peptidomimetic on the BL side, the methylester prodrugs 1b and 2b were approximately 12-fold more able to permeate than were the RGD peptidomimetics la and 2a. When a similar analysis of the transport data for the coumarin prodrugs 3a and 3b was performed, they were shown to be approximately 6-fold and 5-fold more able to permeate than were the RGD peptidomimetics la and 2a, respectively. Conclusions. The coumarin-based cyclic prodrugs 3a and 3b were chemically less stable, but metabolically more stable, than the methylester-based linear prodrugs. The esterase stability of the cyclic prodrugs 3a and 3b means that they are transported intact across the Caco-2 cell monolayer in contrast to the methylester prodrugs 1b and 2b, which undergo facile bioconversion during their transport to the RGD peptidomimetics. However, both prodrug systems successfully delivered more (5-12-fold) of the RGD peptidomimetic and/or the precursor (prodrug) than did the RGD peptidomimetics themselves.     

The discovery and development of boceprevir

Introduction: Boceprevir was the first direct acting agent developed for the treatment of hepatitis C virus infection. Boceprevir functions by targeting NS3 protease, a viral enzyme essential for replication. This peptidomimetic molecule was optimized from a peptide lead to provide a potent, selective and orally bioavailable drug that can be combined with ribavirin and peg interferon to achieve sustained viral response (undetectable HCV RNA levels for 24 weeks after completion of therapy) in patients infected with Genotype 1 of the virus.

Areas covered: This article provides a review of the pre-clinical and clinical discovery of boceprevir. This review includes the role and function of its molecular target, NS3 protease, as well as the assays used to measure in vitro efficacy, compound optimization and clinical studies to demonstrate safety and efficacy.

Expert opinion: As the first direct acting anti-HCV agent, boceprevir represents an important advance in therapy of this widespread chronic disease. Yet, while this therapy is a valuable approach, it does have limitations. Studies have suggested that 30% of patients do not achieve sustained viral response and 11% of patients have developed anemia and/or neutropenia. Current drug discovery and development efforts are underway to develop novel therapeutic options that address these issues.     

复方氟康唑凝胶对耐氟康唑假丝酵母菌的抗菌效果研究

目的 验证复方氟康唑凝胶对耐氟康唑假丝酵母菌的抗菌效果。方法 选用琼脂扩散法,比较复方氟康唑凝胶与氟康唑凝胶对耐氟康唑假丝酵母菌的体外抑菌效果;通过感染耐氟康唑假丝酵母菌大鼠治疗试验,比较复方氟康唑凝胶与氟康唑凝胶治疗效果。结果 复方氟康唑凝胶抑菌圈直径(18.55±0.03)mm（n=20）,氟康唑凝胶抑菌圈直径(7.12±0.01)mm（n=20）,差异具有统计学意义（P<0.05）;复方氟康唑凝胶治疗感染耐氟康唑假丝酵母菌大鼠15d的转阴率为80%,氟康唑凝胶为40%,差异具有统计学意义（P<0.05,n=15）;复方氟康唑凝胶抑制阴道灌洗液炎性细胞因子水平能力、减轻病变损伤程度明显高于氟康唑凝胶（P<0.05,n=15）。结论 复方氟康唑凝胶对耐氟康唑假丝酵母菌的抗菌效果肯定,较氟康唑凝胶具有优势。     

Exploring the stereochemical requirements for protease inhibition by ureidopeptides

Abstract: A novel ‘ureidopeptide’ substrate analog inhibitor of the HIV‐1 protease, created by substitution of a urea for the scissile amide bond of a hexapeptide substrate, was synthesized and tested for inhibition of HIV‐1 protease. This inhibitor was designed as a stereochemical mutant of an earlier ureidopeptide inhibitor in which the P1′ phenylalanine residue was changed from an l ‐isomer to a d ‐isomer. This was done in an attempt to increase binding to the enzyme by compensating for a lengthening of the peptide backbone. The inhibitor was synthesized from two protected tripeptide precursors using an oxidative Hoffmann rearrangement of a C‐terminal peptide amide. The new inhibitor was found to inhibit HIV‐1 protease with an observed IC₅₀ of 47 μm .     

Anti-Candida,docking studies,and in vitro metabolism-mediated cytotoxicity evaluation of Eugenol derivatives

The high morbidity and mortality rates of Candida infections, especially among immunocompromised patients, are related to the increased resistance rate of these species and the limited therapeutic arsenal. In this context, we evaluated the anti-Candida potential and the cytotoxic profile of eugenol derivatives. Anti-Candida activity was evaluated on C. albicans and C. parapsilosis strains by minimum inhibitory concentration (MIC), scanning electron microscopy (SEM), and molecular docking calculations at the site of the enzyme lanosterol-14-α-demethylase active site, responsible for ergosterol formation. The cytotoxic profile was evaluated in HepG2 cells, in the presence and absence of the metabolizing system (S9 system). The results indicated compounds 1b and 1d as the most active ones. The compounds have anti-Candida activity against both strains with MIC ranging from 50 to 100 μg ml⁻¹. SEM analyses of 1b and 1d indicated changes in the envelope architecture of both C. albicans and C. parapsilosis like the ones of eugenol and fluconazole, respectively. Docking results of the evaluated compounds indicated a similar binding pattern of fluconazole and posaconazole at the lanosterol-14-α-demethylase binding site. In the presence of the S9 system, compound 1b showed the same cytotoxicity profile as fluconazole (1.08 times) and compound 1d had 1.23 times increase in cytotoxicity. Eugenol and other evaluated compounds showed a significant increase in cytotoxicity. Our results suggest compound 1b as a promising starting point candidate to be used in the design of new anti-Candida agent prototypes.     

Darunavir: a nonpeptidic protease inhibitor for antiretroviral-naive and treatment-experienced adults with HIV infection

Introduction: Darunavir, a nonpeptidic inhibitor of the HIV-1 protease with potent activity against resistant virus, was initially approved by the FDA (2006) and the EMA (2007) for the treatment of antiretroviral-experienced adults, and later for naive adults. Darunavir/ritonavir (600/100 mg twice daily, ideally given with two other active antiretrovirals) demonstrated superior efficacy compared to lopinavir/ritonavir and other protease inhibitors in highly experienced patients. Darunavir/ritonavir (800/100 mg once daily) was demonstrated to be safe and effective for the treatment of naive patients and those with limited darunavir resistance-associated mutations (RAMs). Because darunavir must be coadministered with ritonavir, cytochrome P450 drug–drug interactions can be problematic.

Areas covered: The chemistry, pharmacokinetics, pharmacodynamics, efficacy and safety of darunavir are reviewed in this paper. A PubMed search was conducted using the search terms ‘randomized’, ‘darunavir’ and ‘efficacy’. Review articles and studies that primarily focused on other drugs were excluded.

Expert opinion: Because darunavir exhibits efficacy against virus with significant protease inhibitor resistance mutations, it is critically important in the treatment of experienced patients, although viral suppression rates may be lower in those with a high baseline viral load or a greater number of cumulative darunavir RAMs. Darunavir/ritonavir is efficacious and well tolerated as a once-daily regimen in naive patients.