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  • 1. Kamte, Stephane L. Ngahang
    et al.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Campagnaro, Gustavo Daniel
    Nya, Prosper C. Biapa
    Mbuntcha, Hélène
    Woguem, Verlaine
    Womeni, Hilaire Macaire
    Tapondjou, Léon Azefack
    Giordani, Cristiano
    Barboni, Luciano
    Benelli, Giovanni
    Cappellacci, Loredana
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Petrelli, Riccardo
    Maggi, Filippo
    Trypanosoma brucei Inhibition by Essential Oils from Medicinal and Aromatic Plants Traditionally Used in Cameroon (Azadirachta indica, Aframomum melegueta, Aframomum daniellii, Clausena anisata, Dichrostachys cinerea and Echinops giganteus)2017In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 14, no 7, article id 737Article in journal (Refereed)
    Abstract [en]

    Essential oils are complex mixtures of volatile components produced by the plant secondary metabolism and consist mainly of monoterpenes and sesquiterpenes and, to a minor extent, of aromatic and aliphatic compounds. They are exploited in several fields such as perfumery, food, pharmaceutics, and cosmetics. Essential oils have long-standing uses in the treatment of infectious diseases and parasitosis in humans and animals. In this regard, their therapeutic potential against human African trypanosomiasis (HAT) has not been fully explored. In the present work, we have selected six medicinal and aromatic plants (Azadirachta indica, Aframomum melegueta, Aframomum daniellii, Clausena anisata, Dichrostachys cinerea, and Echinops giganteus) traditionally used in Cameroon to treat several disorders, including infections and parasitic diseases, and evaluated the activity of their essential oils against Trypanosma brucei TC221. Their selectivity was also determined with Balb/3T3 (mouse embryonic fibroblast cell line) cells as a reference. The results showed that the essential oils from A. indica, A. daniellii, and E. giganteus were the most active ones, with half maximal inhibitory concentration (IC50) values of 15.21, 7.65, and 10.50 mu g/mL, respectively. These essential oils were characterized by different chemical compounds such as sesquiterpene hydrocarbons, monoterpene hydrocarbons, and oxygenated sesquiterpenes. Some of their main components were assayed as well on T. brucei TC221, and their effects were linked to those of essential oils.

  • 2. Kamte, Stephane L. Ngahang
    et al.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Cianfaglione, Kevin
    Sut, Stefania
    Dall'Acqua, Stefano
    Bruno, Maurizio
    Afshar, Fariba Heshmati
    Iannarelli, Romilde
    Benelli, Giovanni
    Cappellacci, Loredana
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Maggi, Filippo
    Petrelli, Riccardo
    Identification of highly effective antitrypanosomal compounds in essential oils from the Apiaceae family2018In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 156, p. 154-165Article in journal (Refereed)
    Abstract [en]

    The Apiaceae family encompasses aromatic plants of economic importance employed in foodstuffs, beverages, perfumery, pharmaceuticals and cosmetics. Apiaceae are rich sources of essential oils because of the wealth of secretory structures (ducts and vittae) they are endowed with. The Apiaceae essential oils are available on an industrial level because of the wide cultivation and disposability of the bulky material from which they are extracted as well as their relatively cheap price. In the fight against protozoal infections, essential oils may represent new therapeutic options. In the present work, we focused on a panel of nine Apiaceae species (Siler montamon, Sison amomum, Echinophora spinosa, Kundmannia sicula, Crithmum maritimum, Helosciadium nodiforum, Pimpinella anisum, Heracleum sphondylium and Trachyspermum cunmi) and their essential oils as a model for the identification of trypanocidal compounds to be used as alternative/integrative therapies in the treatment of Human African trypanosomiasis (HAT) and as starting material for drug design. The evaluation of inhibitory effects of the Apiaceae essential oils against Trypanosoma brucei showed that some of them (E. spinosa, S. amomum, C. maritimwn and H. nodifloruin) were active, with EC50 in the range 2.7-10.7 mu g/mL. Most of these oils were selective against T. brucei, except the one from C. maritimum that was highly selective against the BALB/3T3 mammalian cells. Testing nine characteristic individual components (a-pinene, sabinene, alpha-phellandrene, p-cymene, limonene, beta-ocimene, gamma-terpinene, terpinolene, and myristicin) of these oils, we showed that some of them had much higher selectivity than the oils themselves. Terpinolene was particularly active with an EC50 value of 0.035 mu g/rnL (0.26 mu M) and a selectivity index (SI) of 180. Four other compounds with EC50 in the range 1.0-6.0 mu g/mL (7.4-44 mu M) had also good SI: a-pinene (> 100), beta-ocimene (> 91), limonene (> 18) and sabinene ( > 17). In conclusion, these results highlight that the essential oils from the Apiaceae family are a reservoir of substances to be used as leading compounds for the development of natural drugs for the treatment of HAT.

  • 3. Petrelli, Riccardo
    et al.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Dall'Acqua, Stefano
    Papa, Fabrizio
    Iannarelli, Romilde
    Ngahang Kamte, Stephane L.
    Vittori, Sauro
    Benelli, Giovanni
    Maggi, Filippo
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Cappellacci, Loredana
    An overlooked horticultural crop, Smyrnium olusatrum, as a potential source of compounds effective against African trypanosomiasis2017In: Parasitology international, ISSN 1383-5769, E-ISSN 1873-0329, Vol. 66, no 2, p. 146-151Article in journal (Refereed)
    Abstract [en]

    Among natural products, sesquiterpenes have shown promising inhibitory effects against bloodstream forms of Trypanosoma brucei, the protozoan parasite causing human African trypanosomiasis (HAT). Smyrnium olusatrum (Apiaceae), also known as Alexanders or wild celery, is a neglected horticultural crop characterized by oxygenated sesquiterpenes containing a furan ring. In the present work we explored the potential of its essential oils obtained from different organs and the main oxygenated sesquiterpenes, namely isofuranodiene, germacrone and β-acetoxyfuranoeudesm-4(15)-ene, as inhibitors of Trypanosoma brucei. All essential oils effectively inhibited the growth of parasite showing IC50 values of 1.9–4.0 μg/ml. Among the main essential oil constituents, isofuranodiene exhibited a significant and selective inhibitory activity against T. brucei (IC50 of 0.6 μg/ml, SI = 30), with β-acetoxyfuranoeudesm-4(15)-ene giving a moderate potentiating effect. These results shed light on the possible application of isofuranodiene as an antiprotozoal agent to be included in combination treatments aimed not only at curing patients but also at preventing the diffusion of HAT.

  • 4.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Targets and strategies for drug development against human African sleeping sickness2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Trypanosoma brucei is a causative agent of African sleeping sickness. It is an extracellular parasite which circulates in the blood, lymph and eventually invades the central nervous system. There is a great need for new medicines against the disease and specific properties of nucleoside kinases in the pathogen can be exploited as targets for chemotherapy. 

    T. brucei contains a gene where two thymidine kinase sequences are fused into a single open reading frame. These types of tandem thymidine kinases were found only in different types of parasites, which made us to believe that it might be beneficial for them. Each thymidine kinase sequence in these tandem enzymes are here referred to as a domain. By cloning and expressing each domain from T. brucei separately, we found that domain 1 was inactive and domain 2 was as active as the full-length enzyme. T. brucei thymidine kinase phosphorylated the pyrimidine nucleosides thymidine and deoxyuridine and to some extent purine nucleosides like deoxyinosine and deoxyguanosine. Human thymidine kinase increases the affinity to its substrates when it forms oligomers. Similarly, the T. brucei two thymidine kinase sequences, which can be viewed as a pseudodimer, had a higher affinity to its substrates than domain 2 alone. 

    T. brucei lacks de novo purine biosynthesis and it is therefore dependent on salvaging the required purine nucleotides for RNA and DNA synthesis from the host. Purine salvage is considered as a target for drug development. It has been shown that in the presence of deoxyadenosine in the growth medium, the parasites accumulate high levels of dATP and the extensive phosphorylation of deoxyadenosine leads to depleted ATP pools. Initially, we wondered if deoxyadenosine could be used as a drug against T. brucei. However, we found that T. brucei is partially protected against deoxyadenosine because it was cleaved by the enzyme methylthioadenosine phosphorylase (MTAP) to adenine and ribose-1-phosphate. At higher concentration of deoxyadenosine, 3 the formed adenine was not efficiently salvaged into ATP and started to inhibit MTAP instead. The deoxyadenosine was then instead phosphorylated by adenosine kinase leading to accumulation of dATP. The MTAP reaction makes deoxyadenosine itself useless as a drug and instead we focused on finding analogues of deoxyadenosine or adenosine that were cleavage-resistant and at the same time good substrates of T. brucei adenosine kinase. Our best hit was then 9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl) adenine (FANA-A). An additional advantage of FANA-A as a drug was that it was taken up by the P1 nucleoside transporter family, which makes it useful also against multidrug resistant parasites that often have lost the P2 transporter function and take up their purines solely by the P1 transporter. In parallel with our study of nucleoside metabolism in T. brucei, we also have a collaboration project where we screen essential oils from plants which are used in traditional medicine. If the essential oils are active against the trypanosomes, we further analyze the different components in the oils to identify new drugs against African sleeping sickness. One such compound identified from the plant Smyrnium olusatrum is isofuranodiene, which inhibited T. brucei proliferation with an IC50 value of 3 μM.

  • 5. Ranjbarian, Farahnaz
    et al.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Alzahrani, K. H.
    de Koning, H. P.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    9-(2-Deoxy-2-fluoro-ß-D-arabinofuranosyl) adenine: a potent antitrypanosomal adenosine analogue that circumvents transport-related drug resistanceManuscript (preprint) (Other academic)
  • 6.
    Ranjbarian, Farahnaz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Alzahrani, Khalid J. H.
    Ebiloma, Godwin U.
    de Koning, Harry P.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 6, article id e02719-16Article in journal (Refereed)
    Abstract [en]

    Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. brucei-infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in T. brucei. We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects T. brucei against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC(50)s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.

  • 7.
    Ranjbarian, Farahnaz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Sharvani Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Biochemistry, Institute of Biochemistry and Biophysics, Tehran University, Tehran, Iran.
    Thelander, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Trypanosoma brucei thymidine kinase is tandem protein consisting of two homologous parts, which together enable efficient substrate binding2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 21, p. 17628-17636Article in journal (Refereed)
    Abstract [en]

    Trypanosoma brucei causes African sleeping sickness, a disease for which existing chemotherapies are limited by their toxicity or lack of efficacy. We have found that four parasites, including T. brucei, contain genes where two or four thymidine kinase (TK) sequences are fused into a single open reading frame. The T. brucei full-length enzyme as well as its two constituent parts, domain 1 and domain 2, were separately expressed and characterized. Of potential interest for nucleoside analog development, T. brucei TK was less discriminative against purines than human TK1 with the following order of catalytic efficiencies: thymidine > deoxyuridine ≫ deoxyinosine > deoxyguanosine. Proteins from the TK1 family are generally dimers or tetramers, and the quaternary structure is linked to substrate affinity. T. brucei TK was primarily monomeric but can be considered a two-domain pseudodimer. Independent kinetic analysis of the two domains showed that only domain 2 was active. It had a similar turnover number (k(cat)) as the full-length enzyme but could not self-dimerize efficiently and had a 5-fold reduced thymidine/deoxyuridine affinity. Domain 1, which lacks three conserved active site residues, can therefore be considered a covalently attached structural partner that enhances substrate binding to domain 2. A consequence of the non-catalytic role of domain 1 is that its active site residues are released from evolutionary pressure, which can be advantageous for developing new catalytic functions. In addition, nearly identical 89-bp sequences present in both domains suggest that the exchange of genetic material between them can further promote evolution.

  • 8. Sut, Stefania
    et al.
    Dall'Acqua, Stefano
    Baldan, Valeria
    Ngahang Kamte, Stephane L.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Biapa Nya, Prosper C.
    Vittori, Sauro
    Benelli, Giovanni
    Maggi, Filippo
    Cappellacci, Loredana
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Petrelli, Riccardo
    Identification of tagitinin C from Tithonia diversifolia as antitrypanosomal compound using bioactivity-guided fractionation2018In: Fitoterapia (Milano), ISSN 0367-326X, E-ISSN 1873-6971, Vol. 124, p. 145-151Article in journal (Refereed)
    Abstract [en]

    Tithonia diversifolia (Asteraceae), is used as traditional medicine in tropical countries for the treatment of various diseases, including malaria. Although numerous studies have assessed the antimalarial properties, nothing is known about the effect of T. diversifolia extracts on trypanosomiasis. In this study extracts of T. diversifolia aerial parts were evaluated for their bioactivity against Trypanosoma brucei. The activity was studied against bloodstream forms of T. brucei (TC221), as well as against mammalian cells (BALB/3T3 mouse fibroblasts), as a counter-screen for toxicity. Both methanolic and aqueous extracts showed significant effects with IC50 values of 1.1 and 2.2 mu g/mL against T. brucei (TC221) and 5.2 and 3.7 mu g/mL against BALB/3T3 cells, respectively. A bioassay-guided fractionation on the methanolic extract yielded in identification of active fractions (F8 and F9) with IC50 values of 0.41 and 0.43 mu g/mL, respectively, against T. brucei (TC221) and 1.4 and 1.5 mu g/mL, respectively, against BALB/3T3 cells,. The phytochemical composition of the extracts and the purified fractions were investigated using HPLC-ESI-MS/MS and 1D and 2D NMR spectra showing the presence of sesquiterpene lactones that in turn were subjected to the isolation procedure. Tagitinin A and C were rather active but the latter presented a very strong inhibition on T. brucei (TC221) with an IC50 value of 0.0042 mu g/mL. This activity was 4.5 times better than that of the reference drug suramin. The results of this study shed light on the antitrypanosomal effects of T. diversifolia extracts and highlighted tagitinin C as one of the possible responsible for this effect. Further structure activity relationships studies on tagitinins are needed to consider this sesquiterpenes as lead compounds for the development of new antitrypanosomal drugs.

  • 9. Vande Voorde, Johan
    et al.
    Sabuncuoglu, Suna
    Noppen, Sam
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Fieuws, Steffen
    Balzarini, Jan
    Liekens, Sandra
    Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine2014In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 19, p. 13054-13065Article in journal (Refereed)
    Abstract [en]

    Background: Gemcitabine is used to treat solid tumors. Some mycoplasmas preferentially colonize tumors in patients. Results: Mycoplasma-encoded cytidine deaminase and pyrimidine nucleoside phosphorylase compromise the cytostatic/antitumor activity of gemcitabine in mycoplasma-infected tumor cell cultures and xenografts in mice. Conclusion: Tumor-associated mycoplasmas may decrease the therapeutic efficiency of gemcitabine. Significance: Current treatment of mycoplasma-infected tumors with gemcitabine may be suboptimal. The intracellular metabolism and cytostatic activity of the anticancer drug gemcitabine (2,2-difluoro-2-deoxycytidine; dFdC) was severely compromised in Mycoplasma hyorhinis-infected tumor cell cultures. Pronounced deamination of dFdC to its less cytostatic metabolite 2,2-difluoro-2-deoxyuridine was observed, both in cell extracts and spent culture medium (i.e. tumor cell-free but mycoplasma-containing) of mycoplasma-infected tumor cells. This indicates that the decreased antiproliferative activity of dFdC in such cells is attributed to a mycoplasma cytidine deaminase causing rapid drug catabolism. Indeed, the cytostatic activity of gemcitabine could be restored by the co-administration of tetrahydrouridine (a potent cytidine deaminase inhibitor). Additionally, mycoplasma-derived pyrimidine nucleoside phosphorylase (PyNP) activity indirectly potentiated deamination of dFdC: the natural pyrimidine nucleosides uridine, 2-deoxyuridine and thymidine inhibited mycoplasma-associated dFdC deamination but were efficiently catabolized (removed) by mycoplasma PyNP. The markedly lower anabolism and related cytostatic activity of dFdC in mycoplasma-infected tumor cells was therefore also (partially) restored by a specific TP/PyNP inhibitor (TPI), or by exogenous thymidine. Consequently, no effect on the cytostatic activity of dFdC was observed in tumor cell cultures infected with a PyNP-deficient Mycoplasma pneumoniae strain. Because it has been reported that some commensal mycoplasma species (including M. hyorhinis) preferentially colonize tumor tissue in cancer patients, our findings suggest that the presence of mycoplasmas in the tumor microenvironment could be a limiting factor for the anticancer efficiency of dFdC-based chemotherapy. Accordingly, a significantly decreased antitumor effect of dFdC was observed in mice bearing M. hyorhinis-infected murine mammary FM3A tumors compared with uninfected tumors.

  • 10.
    Vodnala, Munender
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The protective role of Trypanosoma brucei methylthioadenosine phosphorylase against deoxyadenosine and deoxyadenosine analogsManuscript (preprint) (Other academic)
  • 11.
    Vodnala, Munender
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pavlova, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    de Koning, Harry P.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Trypanosoma brucei Methylthioadenosine Phosphorylase Protects the Parasite from the Antitrypanosomal Effect of Deoxyadenosine: IMPLICATIONS FOR THE PHARMACOLOGY OF ADENOSINE ANTIMETABOLITES2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 22, p. 11717-11726Article in journal (Refereed)
    Abstract [en]

    Trypanosoma brucei causes African sleeping sickness for which no vaccine exists and available treatments are of limited use due to their high toxicity or lack of efficacy. T. brucei cultivated in the presence of deoxyadenosine accumulates high levels of dATP in an adenosine kinase-dependent process and dies within a few hours. Here we show that T. brucei treated with 1 mM deoxyadenosine accumulates higher dATP levels than mammalian cells but that this effect diminishes quickly as the concentration of the deoxynucleoside decreases. Radioactive tracer studies showed that the parasites are partially protected against lower concentrations of deoxyadenosine by the ability to cleave it and use the adenine for ATP synthesis. T. brucei methylthioadenosine phosphorylase (TbMTAP) was found to be responsible for the cleavage as indicated by the phosphate dependence of deoxyadenosine cleavage in T. brucei cell extracts and increased deoxyadenosine sensitivity in TbMTAP knockdown cells. Recombinant TbMTAP exhibited higher turnover number (k(cat)) and K-m values for deoxyadenosine than for the regular substrate, methylthioadenosine. One of the reaction products, adenine, inhibited the enzyme, which might explain why TbMTAP-mediated protection is less efficient at higher deoxyadenosine concentrations. Consequently, T. brucei grown in the presence of adenine demonstrated increased sensitivity to deoxyadenosine. For deoxyadenosine/adenosine analogues to remain intact and be active against the parasite, they need to either be resistant to TbMTAP-mediated cleavage, which is the case with the three known antitrypanosomal agents adenine arabinoside, tubercidin, and cordycepin, or they need to be combined with TbMTAP inhibitors.

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