Abstract
Human papillomavirus (HPV) infections are the cause of warts, lesions and cancer, with different types of HPV causing different symptoms. HPV infections are the primary cause of cervical cancer. There are over 220 different types of HPV, and only nine of these can currently be vaccinated. There is a need to treat these viral infections without just treating the symptoms of the infection, as is currently the main method. There is a wide range of small molecules that have been used to inhibit various stages of the HPV infectious cycle. This review examined 132 small molecules from 121 studies that specifically target aspects of HPV infections. HPV DNA encodes for six early genes (E1 to E7, skipping E3) and two late genes (L1 and L2). According to the results, these targets for small molecule inhibitors fall into three categories: those targeting E1 and E2, targeting E6 and E7 and, finally, targeting L1 and L2. Inhibitors of E6 and E7 are the most widely studied targets, with the majority of HPV inhibition in this area. While compounds targeting both E1/E2 and E6/E7 have made it to clinical trials, there has been no significant advancement on the topic.
[PMID: 23093593]
[http://dx.doi.org/10.1016/j.virol.2013.05.012] [PMID: 23769415]
[http://dx.doi.org/10.1016/j.ucl.2015.06.004] [PMID: 26475947]
[http://dx.doi.org/10.1016/S0002-9343(97)00177-0] [PMID: 9217656]
[http://dx.doi.org/10.1097/OLQ.0000000000000193] [PMID: 25299412]
[http://dx.doi.org/10.1093/aje/kwn036] [PMID: 18483125]
[http://dx.doi.org/10.1002/cncr.22751] [PMID: 17487850]
[http://dx.doi.org/10.3389/fonc.2019.00355] [PMID: 31134154]
[http://dx.doi.org/10.1016/S1470-2045(09)70096-8] [PMID: 19350698]
[http://dx.doi.org/10.1093/jnci/djv086] [PMID: 25925419]
[http://dx.doi.org/10.1016/j.ygyno.2017.04.004] [PMID: 28442134]
[http://dx.doi.org/10.1099/vir.0.039677-0] [PMID: 22323530]
[http://dx.doi.org/10.1128/CMR.05028-11] [PMID: 22491770]
[http://dx.doi.org/10.1042/CS20160786] [PMID: 28798073]
[http://dx.doi.org/10.2217/fmb.10.107] [PMID: 21073310]
[http://dx.doi.org/10.1016/j.virol.2010.02.002] [PMID: 20206957]
[http://dx.doi.org/10.1002/cncr.23704] [PMID: 18798536]
[http://dx.doi.org/10.1016/S1473-3099(17)30468-1] [PMID: 28965955]
[http://dx.doi.org/10.1002/path.4424] [PMID: 25124771]
[http://dx.doi.org/10.1177/135965350701200417] [PMID: 17668552]
[http://dx.doi.org/10.2174/1874357901105010080] [PMID: 21769307]
[http://dx.doi.org/10.1080/13543784.2021.2010703] [PMID: 34927502]
[http://dx.doi.org/10.1016/j.virol.2013.07.020] [PMID: 24029589]
[http://dx.doi.org/10.1016/j.virol.2013.06.006] [PMID: 23849793]
[http://dx.doi.org/10.1007/82_2010_92]
[http://dx.doi.org/10.1021/jm034206x] [PMID: 14695816]
[http://dx.doi.org/10.1128/AAC.49.12.4834-4842.2005] [PMID: 16304143]
[http://dx.doi.org/10.2991/iccnce.2013.12]
[http://dx.doi.org/10.1088/1757-899X/335/1/012031]
[http://dx.doi.org/10.1074/jbc.M303608200] [PMID: 12730224]
[http://dx.doi.org/10.1128/jvi.71.5.3853-3863.1997] [PMID: 9094661]
[http://dx.doi.org/10.1016/S0960-894X(03)00510-9] [PMID: 12852961]
[http://dx.doi.org/10.1021/ac035335o] [PMID: 15053675]
[http://dx.doi.org/10.1016/j.bmc.2007.01.036] [PMID: 17306550]
[http://dx.doi.org/10.1074/jbc.M311376200] [PMID: 14634007]
[http://dx.doi.org/10.1016/j.tet.2011.12.047]
[http://dx.doi.org/10.1016/j.tetlet.2015.02.114]
[http://dx.doi.org/10.1002/slct.201702059]
[http://dx.doi.org/10.1021/jm9703404] [PMID: 9379433]
[PMID: 22768354]
[http://dx.doi.org/10.1016/j.bmc.2008.03.053] [PMID: 18396405]
[http://dx.doi.org/10.1002/jmv.24713] [PMID: 27736001]
[http://dx.doi.org/10.1038/onc.2009.78] [PMID: 19421149]
[http://dx.doi.org/10.1128/JVI.03068-12] [PMID: 23365439]
[http://dx.doi.org/10.1371/journal.pone.0077994] [PMID: 24205059]
[http://dx.doi.org/10.3390/v6083228] [PMID: 25140737]
[http://dx.doi.org/10.1016/j.antiviral.2018.03.012] [PMID: 29653131]
[http://dx.doi.org/10.1016/j.virol.2013.07.008] [PMID: 24016539]
[http://dx.doi.org/10.1128/JVI.76.19.9806-9818.2002] [PMID: 12208959]
[http://dx.doi.org/10.1371/journal.ppat.1007788] [PMID: 31091289]
[http://dx.doi.org/10.1128/AAC.00103-09] [PMID: 19398642]
[http://dx.doi.org/10.1159/000292582] [PMID: 20215748]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00659] [PMID: 27933957]
[http://dx.doi.org/10.1016/j.antiviral.2017.12.013] [PMID: 29287913]
[http://dx.doi.org/10.1371/journal.ppat.1006168] [PMID: 28182794]
[PMID: 30707946]
[http://dx.doi.org/10.2174/138920209787581235] [PMID: 19721808]
[http://dx.doi.org/10.1038/sj.onc.1209615] [PMID: 16936740]
[http://dx.doi.org/10.1002/bies.950170607] [PMID: 7575492]
[http://dx.doi.org/10.7314/APJCP.2014.15.19.8007] [PMID: 25338977]
[http://dx.doi.org/10.3390/molecules21081055] [PMID: 27548122]
[http://dx.doi.org/10.1016/j.bmcl.2011.12.145] [PMID: 22300659]
[http://dx.doi.org/10.1371/journal.pone.0084506] [PMID: 24376816]
[http://dx.doi.org/10.1002/j.1460-2075.1991.tb04990.x] [PMID: 1661671]
[http://dx.doi.org/10.1371/journal.pone.0149845] [PMID: 26915086]
[http://dx.doi.org/10.3892/mmr.2019.9850] [PMID: 30664221]
[http://dx.doi.org/10.1038/cddis.2015.391] [PMID: 26794656]
[http://dx.doi.org/10.1021/cb500229d] [PMID: 24854633]
[http://dx.doi.org/10.1002/ptr.6551] [PMID: 31752046]
[http://dx.doi.org/10.1097/00008469-200310000-00007] [PMID: 14512803]
[http://dx.doi.org/10.1089/104454903321655846] [PMID: 12804120]
[http://dx.doi.org/10.1007/s12272-009-1917-3] [PMID: 19784588]
[http://dx.doi.org/10.3390/molecules23092334] [PMID: 30213130]
[http://dx.doi.org/10.1007/s00280-012-2063-z] [PMID: 23292117]
[http://dx.doi.org/10.1007/s40675-017-0062-7] [PMID: 28944164]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2704] [PMID: 17473185]
[http://dx.doi.org/10.1016/j.biochi.2015.11.008] [PMID: 26586108]
[PMID: 9816335]
[http://dx.doi.org/10.3390/nu10020243] [PMID: 29485619]
[http://dx.doi.org/10.3389/fonc.2019.00352] [PMID: 31143704]
[http://dx.doi.org/10.3892/ijmm.2020.4789] [PMID: 33236130]
[http://dx.doi.org/10.1002/biof.1344] [PMID: 27896883]
[http://dx.doi.org/10.1002/mc.20170] [PMID: 16526022]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00975] [PMID: 28074653]
[http://dx.doi.org/10.18632/oncotarget.6383] [PMID: 26621832]
[http://dx.doi.org/10.1186/s13048-021-00789-x] [PMID: 33706784]
[http://dx.doi.org/10.1016/j.canlet.2019.11.035] [PMID: 31809801]
[http://dx.doi.org/10.1016/j.molstruc.2020.129865]
[http://dx.doi.org/10.1111/j.1525-1438.2006.00726.x] [PMID: 17177841]
[http://dx.doi.org/10.1016/j.bcp.2014.02.011] [PMID: 24565908]
[http://dx.doi.org/10.1016/S1357-2725(99)00024-2] [PMID: 10687948]
[http://dx.doi.org/10.1038/s41598-019-56410-1] [PMID: 31889069]
[http://dx.doi.org/10.1016/j.tiv.2019.02.022] [PMID: 30822460]
[http://dx.doi.org/10.18632/oncotarget.27908] [PMID: 33796223]
[http://dx.doi.org/10.1002/cbdv.200690000] [PMID: 17193222]
[http://dx.doi.org/10.1093/carcin/bgr192] [PMID: 21859835]
[http://dx.doi.org/10.1016/j.oraloncology.2014.09.013] [PMID: 25311433]
[http://dx.doi.org/10.1016/j.canlet.2014.09.037] [PMID: 25304375]
[http://dx.doi.org/10.1080/13102818.2019.1677175]
[http://dx.doi.org/10.1186/1476-4598-10-39] [PMID: 21496227]
[http://dx.doi.org/10.1038/sj.onc.1204383] [PMID: 11402335]
[http://dx.doi.org/10.1016/j.ejphar.2014.09.048] [PMID: 25448308]
[http://dx.doi.org/10.1177/1087057114536987] [PMID: 24874507]
[http://dx.doi.org/10.1016/j.ejmech.2019.111951] [PMID: 31821990]
[http://dx.doi.org/10.1002/ptr.6687] [PMID: 32364634]
[http://dx.doi.org/10.1093/jnci/91.14.1211] [PMID: 10413422]
[http://dx.doi.org/10.1016/S0968-0896(00)00193-0] [PMID: 11092540]
[http://dx.doi.org/10.1016/j.chembiol.2012.03.007] [PMID: 22520758]
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2787] [PMID: 20395210]
[http://dx.doi.org/10.1097/CAD.0000000000000357] [PMID: 26945135]
[http://dx.doi.org/10.1007/s10637-019-00848-7] [PMID: 31432292]
[http://dx.doi.org/10.1016/j.canlet.2019.10.046] [PMID: 31693922]
[http://dx.doi.org/10.1073/pnas.97.15.8501] [PMID: 10900010]
[http://dx.doi.org/10.1038/srep42180] [PMID: 28176847]
[http://dx.doi.org/10.7164/antibiotics.30.275] [PMID: 863788]
[http://dx.doi.org/10.1016/0040-4039(94)88036-0]
[http://dx.doi.org/10.1038/sj.cdd.4400796] [PMID: 11319606]
[http://dx.doi.org/10.1016/S0248-4900(02)01220-0] [PMID: 12753950]
[PMID: 21036719]
[http://dx.doi.org/10.1016/0040-4039(96)01844-8]
[http://dx.doi.org/10.1016/j.canlet.2008.06.030] [PMID: 18687520]
[http://dx.doi.org/10.1016/j.antiviral.2006.03.014] [PMID: 16690141]
[http://dx.doi.org/10.1038/ncponc0354] [PMID: 16341240]
[http://dx.doi.org/10.1016/j.virol.2007.12.016] [PMID: 18242658]
[http://dx.doi.org/10.1371/journal.pone.0141245] [PMID: 26509736]
[http://dx.doi.org/10.18632/oncotarget.10631] [PMID: 28881717]
[http://dx.doi.org/10.1186/1476-4598-13-80] [PMID: 24708873]
[http://dx.doi.org/10.18632/oncotarget.17575] [PMID: 28521287]
[PMID: 31897221]
[http://dx.doi.org/10.1016/j.gene.2014.10.007] [PMID: 25300249]
[http://dx.doi.org/10.1038/sj.onc.1207620] [PMID: 15077164]
[http://dx.doi.org/10.1038/s41598-018-24470-4] [PMID: 29662081]
[http://dx.doi.org/10.1371/journal.pone.0155909]
[http://dx.doi.org/10.1186/s12985-017-0806-5] [PMID: 28754129]
[http://dx.doi.org/10.1186/s13008-018-0040-6] [PMID: 30250494]
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0506] [PMID: 26516156]
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0159] [PMID: 28522591]
[http://dx.doi.org/10.1016/j.oraloncology.2018.09.006] [PMID: 30409290]
[PMID: 33163279]
[http://dx.doi.org/10.3390/ijms20215455] [PMID: 31683862]
[http://dx.doi.org/10.1021/jm100589p] [PMID: 21186794]
[http://dx.doi.org/10.1016/j.ccr.2013.11.001] [PMID: 24332045]
[http://dx.doi.org/10.1007/s00044-017-1891-0]
[http://dx.doi.org/10.4161/cc.23882] [PMID: 23421999]
[http://dx.doi.org/10.3892/or.2014.3082] [PMID: 24627094]
[http://dx.doi.org/10.1177/154407370601900120] [PMID: 16672559]
[http://dx.doi.org/10.1177/135965350601100607] [PMID: 17310826]
[http://dx.doi.org/10.1039/b923046g] [PMID: 20390218]
[http://dx.doi.org/10.1007/s00216-010-4283-6] [PMID: 20957472]
[http://dx.doi.org/10.3851/IMP1786] [PMID: 21685539]
[http://dx.doi.org/10.1089/jir.2013.0147] [PMID: 24697205]
[http://dx.doi.org/10.1016/j.antiviral.2011.05.016] [PMID: 21669231]
[http://dx.doi.org/10.3390/cancers13050949] [PMID: 33668328]
[http://dx.doi.org/10.3892/ol.2016.5008] [PMID: 27698818]
[PMID: 27330277]
[http://dx.doi.org/10.1038/srep43373] [PMID: 28252027]
[http://dx.doi.org/10.1016/j.ejphar.2019.01.045] [PMID: 30695683]
[http://dx.doi.org/10.1016/j.biopha.2019.109762] [PMID: 31864213]
[http://dx.doi.org/10.1186/s13046-020-01627-6] [PMID: 32631421]
[http://dx.doi.org/10.3892/mmr.2020.11725] [PMID: 33236135]
[http://dx.doi.org/10.1002/ijc.33594] [PMID: 33844847]
[http://dx.doi.org/10.1021/jm500340h] [PMID: 24905115]
[http://dx.doi.org/10.1128/mBio.01104-14] [PMID: 25096873]
[http://dx.doi.org/10.1016/j.virol.2004.03.033] [PMID: 15183049]
[http://dx.doi.org/10.1016/j.virol.2013.05.038] [PMID: 23800545]
[http://dx.doi.org/10.1016/j.virol.2013.04.017] [PMID: 23689062]
[http://dx.doi.org/10.1039/c3cc49789e] [PMID: 24522285]
[http://dx.doi.org/10.1002/slct.201601467]
[http://dx.doi.org/10.1080/10610278.2020.1779930]
[http://dx.doi.org/10.1128/JVI.00998-07] [PMID: 17686860]
[http://dx.doi.org/10.1371/journal.ppat.1002519] [PMID: 22346752]
[http://dx.doi.org/10.1128/AAC.02284-13] [PMID: 24614368]
[http://dx.doi.org/10.1128/JVI.01081-10] [PMID: 20702627]
[http://dx.doi.org/10.1016/j.virol.2010.09.002] [PMID: 20875908]
[http://dx.doi.org/10.1371/journal.pone.0097232] [PMID: 24816794]
[http://dx.doi.org/10.1073/pnas.0508815103] [PMID: 16432208]
[http://dx.doi.org/10.1016/j.antiviral.2011.12.007] [PMID: 22197636]
[http://dx.doi.org/10.1177/2472555219860771] [PMID: 31361520]