Aspartic Peptidase of As Target of HIV Peptidase Inhibitors: Blockage of Its Enzymatic Activity and Interference with Fungal Growth and Macrophage Interaction

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2020 Feb 11

PMID 32037904

Citations 5

Authors

Marcela Q Granato

Ingrid S Sousa

Thabatta L S A Rosa

Diego S Goncalves

Sergio H Seabra

Daniela S Alviano

Maria C V Pessolani

Andre L S Santos

Lucimar F Kneipp

Affiliations

Soon will be listed here.

Abstract

causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.

Citing Articles

Silver(I) 1,10-Phenanthroline Complexes Are Active against Viability and Negatively Modulate Its Potential Virulence Attributes.

Sousa I, Vieira T, Menna-Barreto R, Guimaraes A, McCarron P, McCann M J Fungi (Basel). 2023; 9(3).

PMID: 36983524 PMC: 10057124. DOI: 10.3390/jof9030356.

Biofilm Formation by Chromoblastomycosis Fungi and : Involvement with Antifungal Resistance.

Sousa I, Mello T, Pereira E, Granato M, Alviano C, Santos A J Fungi (Basel). 2022; 8(9).

PMID: 36135688 PMC: 9504689. DOI: 10.3390/jof8090963.

Lopinavir-menthol co-crystals for enhanced dissolution rate and intestinal absorption.

Fayed N, Arafa M, Essa E, El Maghraby G J Drug Deliv Sci Technol. 2022; 74:103587.

PMID: 35845293 PMC: 9272570. DOI: 10.1016/j.jddst.2022.103587.

Reviewing the Etiologic Agents, Microbe-Host Relationship, Immune Response, Diagnosis, and Treatment in Chromoblastomycosis.

Passero L, Cavallone I, Belda Jr W J Immunol Res. 2021; 2021:9742832.

PMID: 34761009 PMC: 8575639. DOI: 10.1155/2021/9742832.

Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from -In Silico, In Vitro and In Vivo Approaches.

Santos A, Braga-Silva L, Goncalves D, Ramos L, Oliveira S, Souza L J Fungi (Basel). 2021; 7(6).

PMID: 34071195 PMC: 8229492. DOI: 10.3390/jof7060424.

References

Palmeira V, Kneipp L, Rozental S, Alviano C, Santos A . Beneficial effects of HIV peptidase inhibitors on Fonsecaea pedrosoi: promising compounds to arrest key fungal biological processes and virulence. PLoS One. 2008; 3(10):e3382. PMC: 2557140. DOI: 10.1371/journal.pone.0003382. View

de Aguiar Cordeiro R, Serpa R, Mendes P, Evangelista A, Andrade A, Silva Franco J . The HIV aspartyl protease inhibitor ritonavir impairs planktonic growth, biofilm formation and proteolytic activity in Trichosporon spp. Biofouling. 2017; 33(8):640-650. DOI: 10.1080/08927014.2017.1350947. View

Granato M, Massapust P, Rozental S, Alviano C, Dos Santos A, Kneipp L . 1,10-phenanthroline inhibits the metallopeptidase secreted by Phialophora verrucosa and modulates its growth, morphology and differentiation. Mycopathologia. 2014; 179(3-4):231-42. DOI: 10.1007/s11046-014-9832-7. View

Cui J, Ren B, Tong Y, Dai H, Zhang L . Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans. Virulence. 2015; 6(4):362-71. PMC: 4601232. DOI: 10.1080/21505594.2015.1039885. View

Braga-Silva L, Santos A . Aspartic protease inhibitors as potential anti-Candida albicans drugs: impacts on fungal biology, virulence and pathogenesis. Curr Med Chem. 2011; 18(16):2401-19. DOI: 10.2174/092986711795843182. View

Dos Santos A . Protease expression by microorganisms and its relevance to crucial physiological/pathological events. World J Biol Chem. 2011; 2(3):48-58. PMC: 3083995. DOI: 10.4331/wjbc.v2.i3.48. View

Palmeira V, Alviano D, Braga-Silva L, Goulart F, Granato M, Rozental S . HIV Aspartic Peptidase Inhibitors Modulate Surface Molecules and Enzyme Activities Involved with Physiopathological Events in . Front Microbiol. 2017; 8:918. PMC: 5437157. DOI: 10.3389/fmicb.2017.00918. View

Cassone A, De Bernardis F, Torosantucci A, Tacconelli E, Tumbarello M, Cauda R . In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors. J Infect Dis. 1999; 180(2):448-53. DOI: 10.1086/314871. View

Seyedmousavi S, Netea M, Mouton J, Melchers W, Verweij P, de Hoog G . Black yeasts and their filamentous relatives: principles of pathogenesis and host defense. Clin Microbiol Rev. 2014; 27(3):527-42. PMC: 4135901. DOI: 10.1128/CMR.00093-13. View

10.

Hayakawa M, Ghosn E, da Gloria Teixeria de Sousa M, Ferreira K, Almeida S . Phagocytosis, production of nitric oxide and pro-inflammatory cytokines by macrophages in the presence of dematiaceous [correction of dematiaceus] fungi that cause chromoblastomycosis. Scand J Immunol. 2006; 64(4):382-7. DOI: 10.1111/j.1365-3083.2006.01804.x. View

11.

Kneipp L, Rodrigues M, Holandino C, Esteves F, Souto-Padron T, Alviano C . Ectophosphatase activity in conidial forms of Fonsecaea pedrosoi is modulated by exogenous phosphate and influences fungal adhesion to mammalian cells. Microbiology (Reading). 2004; 150(Pt 10):3355-62. DOI: 10.1099/mic.0.27405-0. View

12.

Mandujano-Gonzalez V, Villa-Tanaca L, Anducho-Reyes M, Mercado-Flores Y . Secreted fungal aspartic proteases: A review. Rev Iberoam Micol. 2016; 33(2):76-82. DOI: 10.1016/j.riam.2015.10.003. View

13.

Torres-Guerrero E, Isa-Isa R, Isa M, Arenas R . Chromoblastomycosis. Clin Dermatol. 2012; 30(4):403-8. DOI: 10.1016/j.clindermatol.2011.09.011. View

14.

Santos L, Vitorio B, Branquinha M, Pedroso e Silva C, Santos A, dAvila-Levy C . Nelfinavir is effective in inhibiting the multiplication and aspartic peptidase activity of Leishmania species, including strains obtained from HIV-positive patients. J Antimicrob Chemother. 2012; 68(2):348-53. PMC: 3543121. DOI: 10.1093/jac/dks410. View

15.

Palmeira V, Kneipp L, Alviano C, Dos Santos A . Secretory aspartyl peptidase activity from mycelia of the human fungal pathogen Fonsecaea pedrosoi: effect of HIV aspartyl proteolytic inhibitors. Res Microbiol. 2006; 157(9):819-26. DOI: 10.1016/j.resmic.2006.07.003. View

16.

Dos Santos A . HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos. World J Biol Chem. 2011; 1(2):21-30. PMC: 3083943. DOI: 10.4331/wjbc.v1.i2.21. View

17.

De Clercq E . Antivirals: past, present and future. Biochem Pharmacol. 2012; 85(6):727-44. DOI: 10.1016/j.bcp.2012.12.011. View

18.

Li Y, Xiao J, de Hoog G, Wang X, Wan Z, Yu J . Biodiversity and human-pathogenicity of and relatives in . Persoonia. 2017; 38:1-19. PMC: 5645179. DOI: 10.3767/003158517X692779. View

19.

Santos A, Palmeira V, Rozental S, Kneipp L, Nimrichter L, Alviano D . Biology and pathogenesis of Fonsecaea pedrosoi, the major etiologic agent of chromoblastomycosis. FEMS Microbiol Rev. 2007; 31(5):570-91. DOI: 10.1111/j.1574-6976.2007.00077.x. View

20.

Clarke S, Dumesic P, Homer C, ODonoghue A, La Greca F, Pallova L . Integrated Activity and Genetic Profiling of Secreted Peptidases in Cryptococcus neoformans Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence. PLoS Pathog. 2016; 12(12):e1006051. PMC: 5158083. DOI: 10.1371/journal.ppat.1006051. View