A clinically used anti-human papilloma virus agent (3-hydroxyphthalic anhydride-modified bovine β-lactoglobulin) has a potential for topical application to prevent sexual transmission of monkeypox virus

Abstract

A global outbreak of monkeypox (mpox) caused by the mpox virus (MPXV) has posed a serious threat to public health worldwide, thus calling for the urgent development of antivirals and vaccines to curb its further spread. In this study, we screened 41 anhydride-modified proteins and found that 3-hydroxyphthalic anhydride-modified β-lactoglobulin (3HP-β-LG), a clinically used anti-HPV agent, was highly effective in inhibiting infection of vaccinia virus Tiantan strain (VACV-VTT) and MPXV. Mechanistic studies demonstrated that 3HP-β-LG bound to the virus, not the host cell, by targeting the early stage of virus entry, possibly through the interaction between the amino acids with negatively charges in 3HP-β-LG and the key amino acids with positive charges in the target region of A29L, a key surface protein of MPXV. A synergistic effect was observed when 3HP-β-LG was combined with tecovirimat, a small-molecule antiviral drug approved by the United States Food and Drug Administration and the European Medicine Agency for the treatment of smallpox and mpox. Because of its clinically proven safety and stability, 3HP-β-LG shows promise for further development as a prophylactic agent to prevent the sexual transmission of MPXV.

Keywords

antiviral agent / monkeypox virus / sexual transmission / vaccinia virus Tiantan strain

References

[1] Xia A, Wang X, He J, et al. Cross-reactive antibody response to Monkeypox virus surface proteins in a small proportion of individuals with and without Chinese smallpox vaccination history. BMC Biol. 2023; 21(1): 205.

[2] Gessain A, Nakoune E, Monkeypox YazdanpanahY. N Engl J Med. 2022; 387(19): 1783-1793.

[3] Li M, Guo Y, Deng Y, et al. Long-lasting humoral and cellular memory immunity to vaccinia virus Tiantan provides pre-existing immunity against mpox virus in Chinese population. Cell Rep. 2024; 43(1): 113609.

[4] Gilchuk I, Gilchuk P, Sapparapu G, et al. Cross-neutralizing and protective human antibody specificities to poxvirus infections. Cell. 2016; 167(3): 684-694. e689.

[5] Zhang Q, Tian M, Feng Y, et al. Genomic sequence and virulence of clonal isolates of vaccinia virus Tiantan, the Chinese smallpox vaccine strain. PLoS One. 2013; 8(4): e60557.

[6] Lum FM, Torres-Ruesta A, Tay MZ, et al. Monkeypox: disease epidemiology, host immunity and clinical interventions. Nat Rev Immunol. 2022; 22(10): 597-613.

[7] Bojkova D, Bechtel M, Rothenburger T, et al. Drug sensitivity of currently circulating mpox viruses. N Engl J Med. 2023; 388(3): 279-281.

[8] Chan-Tack K, Harrington P, Bensman T, et al. Benefit-risk assessment for brincidofovir for the treatment of smallpox: U.S. Food and Drug Administration’s evaluation. Antiviral Res. 2021; 195: 105182.

[9] Fox T, Gould S, Princy N, Rowland T, Lutje V, Kuehn R. Therapeutics for treating mpox in humans. Cochrane Database Syst Rev. 2023; 3(3): CD015769.

[10] Shiryaev VA, Skomorohov MY, Leonova MV, et al. Adamantane derivatives as potential inhibitors of p37 major envelope protein and poxvirus reproduction. Design, synthesis and antiviral activity. Eur J Med Chem. 2021; 221: 113485.

[11] Islam MR, Hossain MJ, Roy A, et al. Repositioning potentials of smallpox vaccines and antiviral agents in monkeypox outbreak: a rapid review on comparative benefits and risks. Health Sci Rep. 2022; 5(5): e798.

[12] Neurath AR, Debnath AK, Strick N, Li YY, Lin K, Jiang S. Blocking of CD4 cell receptors for the human immunodeficiency virus type 1 (HIV-1) by chemically modified bovine milk proteins: potential for AIDS prophylaxis. J Mol Recognit. 1995; 8(5): 304-316.

[13] Neurath AR, Jiang S, Strick N, Lin K, Li YY, Debnath AK. Bovine beta-lactoglobulin modified by 3-hydroxyphthalic anhydride blocks the CD4 cell receptor for HIV. Nat Med. 1996; 2(2): 230-234.

[14] Lu L, Yang X, Li Y, Jiang S. Chemically modified bovine beta-lactoglobulin inhibits human papillomavirus infection. Microbes Infect. 2013; 15(6-7): 506-510.

[15] Hua C, Zhu Y, Wu C, et al. The underlying mechanism of 3-hydroxyphthalic anhydride-modified bovine beta-lactoglobulin to block human papillomavirus entry into the host cell. Front Microbiol. 2019; 10: 2188.

[16] Hua C, Ma Q, Zhu Y, et al. Repurposing of a clinically used anti-HPV agent to prevent and treat SARS-CoV-2 infection as an intranasal formulation. Signal Transduct Target Ther. 2021; 6(1): 318.

[17] Fu Y, Li P, Xu W, et al. Chemically modified bovine beta-lactoglobulin as a broad-spectrum influenza virus entry inhibitor with the potential to combat influenza outbreaks. Viruses. 2022; 14(9).

[18] Guo X, Qiu L, Wang Y, et al. A randomized open-label clinical trial of an anti-HPV biological dressing (JB01-BD) administered intravaginally to treat high-risk HPV infection. Microbes Infect. 2016; 18(2): 148-152.

[19] Zhao F, Hu Y, Fan Z, et al. Rapid and sensitive one-tube detection of mpox virus using RPA-coupled CRISPR-Cas12 assay. Cell Rep Methods. 2023; 3(10): 100620.

[20] Alakunle E, Moens U, Nchinda G, Okeke MI. Monkeypox virus in Nigeria: infection biology, epidemiology, and evolution. Viruses. 2020; 12(11).

[21] Buller RM, Palumbo GJ. Poxvirus pathogenesis. Microbiol Rev. 1991; 55(1): 80-122.

[22] Amanna IJ, Slifka MK, Crotty S. Immunity and immunological memory following smallpox vaccination. Immunol Rev. 2006; 211: 320-337.

[23] Wang Y, Yang K, Zhou H. Immunogenic proteins and potential delivery platforms for mpox virus vaccine development: a rapid review. Int J Biol Macromol. 2023; 245: 125515.

[24] He P, Shi D, Li Y, et al. SPR sensor-based analysis of the inhibition of marine sulfated glycans on interactions between monkeypox virus proteins and glycosaminoglycans. Mar Drugs. 2023; 21(5).

[25] Vanderlinden E, Boonen A, Noppen S, et al. PRO-2000 exhibits SARS-CoV-2 antiviral activity by interfering with spike-heparin binding. Antiviral Res. 2023; 217: 105700.

[26] Tang H, Zhang A. Human mpox: biology, epidemiology, therapeutic options, and development of small molecule inhibitors. Med Res Rev. 2023; 43(4): 1019-1037.

[27] Li L, He L, Tan S, et al. 3-hydroxyphthalic anhydride-modified chicken ovalbumin exhibits potent and broad anti-HIV-1 activity: a potential microbicide for preventing sexual transmission of HIV-1. Antimicrob Agents Chemother. 2010; 54(5): 1700-1711.

[28] Huang B, Zhao H, Song J, et al. Isolation and characterization of monkeypox virus from the first case of monkeypox—Chongqing Municipality, China, 2022. China CDC Wkly. 2022; 4(46): 1019-1024.

[29] Maksyutov RA, Gavrilova EV, Shchelkunov SN. Species-specific differentiation of variola, monkeypox, and varicella-zoster viruses by multiplex real-time PCR assay. J Virol Methods. 2016; 236: 215-220.

[30] Chu Q, Huang B, Li M, et al. Non-replicating vaccinia virus NTV as an effective next-generation smallpox and monkeypox vaccine: evidence from mouse and rhesus monkey models. Emerg Microbes Infect. 2023; 12(2): 2278900.

[31] Mills MG, Juergens KB, Gov JP, et al. Evaluation and clinical validation of monkeypox (mpox) virus real-time PCR assays. J Clin Virol. 2023; 159: 105373.

[32] Pan C, Cai L, Lu H, Qi Z, Jiang S. Combinations of the first and next generations of human immunodeficiency virus (HIV) fusion inhibitors exhibit a highly potent synergistic effect against enfuvirtide-sensitive and -resistant HIV type 1 strains. J Virol. 2009; 83(16): 7862-7872.

[33] Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22: 27-55.

[34] Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596(7873): 583-589.

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