The Experts below are selected from a list of 17466 Experts worldwide ranked by ideXlab platform
Shibo Jiang - One of the best experts on this subject based on the ideXlab platform.
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Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41
Viruses, 2019Co-Authors: Qian Wang, Shibo JiangAbstract:Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of action different from those of the current ARDs. The first peptide-based HIV Entry inhibitor, enfuvirtide, was approved by the U.S. FDA in 2003 for treatment of HIV/AIDS patients who have failed to respond to the current ARDs, which has stimulated the development of several series of protein- and peptide-based HIV Entry Inhibitors in preclinical and clinical studies. In this review, we highlighted the properties and mechanisms of action for those promising protein- and peptide-based HIV Entry Inhibitors targeting the HIV-1 gp120 or gp41 and discussed their advantages and disadvantages, compared with the current ARDs.
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Small-molecule HIV-1 Entry Inhibitors targeting gp120 and gp41: a patent review (2010-2015).
Expert opinion on therapeutic patents, 2017Co-Authors: Shibo JiangAbstract:ABSTRACTIntroduction: It is essential to discover and develop small-molecule HIV-1 Entry Inhibitors with suitable pharmaceutical properties.Areas covered: We review the development of small-molecule HIV-1 Entry Inhibitors as evidenced in patents, patent applications, and related research articles published between 2010 and 2015.Expert opinion: HIV-1 Env gp120 and gp41 are important targets for development of HIV-1 Entry Inhibitors. The Phe43 pocket in gp120 and the highly conserved hydrophobic pocket on gp41 NHR-trimer are important targets for identification of HIV-1 attachment and fusion Inhibitors, respectively. Compounds that bind to Phe43 pocket can block viral gp120 binding to CD4 on T cells, thus inhibiting HIV-1 attachment. However, most compounds targeting Phe43 pocket identified so far are HIV-1 Entry agonists with the ability to enhance infectivity of HIV-1 in CD4-negative cells. Therefore, it is essential to identify HIV-1 Entry antagonist-based HIV-1 attachment/Entry Inhibitors. Compounds bin...
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Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41.
Current topics in medicinal chemistry, 2015Co-Authors: Lifeng Cai, Asim K. Debnath, Shibo JiangAbstract:Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 Entry, thus serving as key targets for the development of HIV-1 Entry Inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV Entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV Entry Inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV Entry inhibitor candidates and further predicted the future trend of HIV Entry inhibitor development.
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Development of peptidic MERS-CoV Entry Inhibitors
Yao xue xue bao = Acta pharmaceutica Sinica, 2015Co-Authors: Shuai Xia, Qian Wang, Shu Wen Liu, Shibo JiangAbstract:In 2012, a new SARS-like coronavirus emerged in the Middle East, namely the Middle East respiratory syndrome coronavirus (MERS-CoV). It has caused outbreaks with high mortality. During infection of target cell, MERS-CoV S protein S1 subunit binds to the cellular receptor (DPP4), and its S2 subunit HR1 and HR2 regions intact with each other to form a stable six-helix bundle to mediate the fusion between virus and target cell membranes. Hence, blocking the process of six-helix bundle formation can effectively inhibit MERS-CoV Entry into the target cells. This review focuses on the recent advance in the development of peptidic Entry Inhibitors targeting the MERS-CoV S2 subunit.
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a safe and convenient pseudovirus based inhibition assay to detect neutralizing antibodies and screen for viral Entry Inhibitors against the novel human coronavirus mers cov
Virology Journal, 2013Co-Authors: Guangyu Zhao, Lanying Du, Vincent K M Poon, Bojian Zheng, Fei Yu, Ye Li, Shibo Jiang, Lili Wang, Lin LiAbstract:Background: Evidence points to the emergence of a novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), which causes a severe acute respiratory syndrome (SARS)-like disease. In response, the development of effective vaccines and therapeutics remains a clinical priority. To accomplish this, it is necessary to evaluate neutralizing antibodies and screen for MERS-CoV Entry Inhibitors. Methods: In this study, we produced a pseudovirus bearing the full-length spike (S) protein of MERS-CoV in the Env-defective, luciferase-expressing HIV-1 backbone. We then established a pseudovirus-based inhibition assay to detect neutralizing antibodies and anti-MERS-CoV Entry Inhibitors. Results: Our results demonstrated that the generated MERS-CoV pseudovirus allows for single-cycle infection of a variety of cells expressing dipeptidyl peptidase-4 (DPP4), the confirmed receptor for MERS-CoV. Consistent with the results from a live MERS-CoV-based inhibition assay, the antisera of mice vaccinated with a recombinant protein containing receptor-binding domain (RBD, residues 377–662) of MERS-CoV S fused with Fc of human IgG exhibited neutralizing antibody response against infection of MERS-CoV pseudovirus. Furthermore, one small molecule HIV Entry inhibitor targeting gp41 (ADS-J1) and the 3-hydroxyphthalic anhydride-modified human serum albumin (HP-HSA) could significantly inhibit MERS-CoV pseudovirus infection. Conclusion: Taken together, the established MERS-CoV inhibition assay is a safe and convenient pseudovirus-based alternative to BSL-3 live-virus restrictions and can be used to rapidly screen MERS-CoV Entry Inhibitors, as well as evaluate vaccine-induced neutralizing antibodies against the highly pathogenic MERS-CoV.
Asim K. Debnath - One of the best experts on this subject based on the ideXlab platform.
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Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41.
Current topics in medicinal chemistry, 2015Co-Authors: Lifeng Cai, Asim K. Debnath, Shibo JiangAbstract:Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 Entry, thus serving as key targets for the development of HIV-1 Entry Inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV Entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV Entry Inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV Entry inhibitor candidates and further predicted the future trend of HIV Entry inhibitor development.
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Rational design of HIV-1 Entry Inhibitors.
Methods in molecular biology (Clifton N.J.), 2013Co-Authors: Asim K. DebnathAbstract:This chapter reviews studies that have used in silico techniques to design or identify potential HIV-1 Entry Inhibitors targeting cellular receptors CD4, CCR5, and CXCR4 and envelope glycoproteins, gp120 and gp41 of HIV-1. Both structure- and ligand-based design techniques have been used in those studies by applying diverse modeling techniques such as quantitative structure-activity relationship analysis, conformational analysis, molecular dynamics, pharmacophore generation, docking, virtual screening (using docking software and also shape-based ROCS techniques), and fragment-based design.
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Approaches for identification of HIV-1 Entry Inhibitors targeting gp41 pocket.
Viruses, 2013Co-Authors: Xiaojie Zhu, Asim K. Debnath, Shibo JiangAbstract:The hydrophobic pocket in the HIV-1 gp41 N-terminal heptad repeat (NHR) domain plays an important role in viral fusion and Entry into the host cell, and serves as an attractive target for development of HIV-1 fusion/Entry Inhibitors. The peptide anti-HIV drug targeting gp41 NHR, T-20 (generic name: enfuvirtide; brand name: Fuzeon), was approved by the U.S. FDA in 2003 as the first HIV fusion/Entry inhibitor for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, because T20 lacks the pocket-binding domain (PBD), it exhibits low anti-HIV-1 activity and short half-life. Therefore, several next-generation HIV fusion inhibitory peptides with PBD have been developed. They possess longer half-life and more potent antiviral activity against a broad spectrum of HIV-1 strains, including the T-20-resistant variants. Nonetheless, the clinical application of these peptides is still limited by the lack of oral availability and the high cost of production. Thus, development of small molecule compounds targeting the gp41 pocket with oral availability has been promoted. This review describes the main approaches for identification of HIV fusion/Entry Inhibitors targeting the gp41 pocket and summarizes the latest progress in developing these Inhibitors as a new class of anti-HIV drugs.
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Development of HIV Entry Inhibitors targeted to the coiled-coil regions of gp41.
Biochemical and biophysical research communications, 2000Co-Authors: Shibo Jiang, Asim K. DebnathAbstract:The discoveries that synthetic peptides corresponding to the N- and C-terminal heptad repeat (HR) regions of gp41 have potent anti-HIV activity opened a new avenue to identification of small molecule HIV Entry Inhibitors targeted to the HIV gp41 coiled-coil regions. Based on the structural information of the HIV gp41 core, three distinct approaches to develop small molecule anti-HIV agents have been reported. Each of these approaches has specific advantages, which will have complementary effects on the design of new strategies for identification of more potent HIV Entry Inhibitors. It is expected that novel antiviral drugs targeted to the HIV gp41 coiled-coil regions will be developed in the near future for the chemotherapy and/or prophylaxis of HIV infection and AIDS.
Lijun Rong - One of the best experts on this subject based on the ideXlab platform.
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Development of coumarine derivatives as potent anti-filovirus Entry Inhibitors targeting viral glycoprotein.
European journal of medicinal chemistry, 2020Co-Authors: Yinyi Gao, Han Cheng, Lijun Rong, Sameer Khan, Gaokeng Xiao, Chuan BaiAbstract:Abstract Filoviruses, including Ebolavirus (EBOV), Marburgvirus (MARV) and Cuevavirus, cause hemorrhagic fevers in humans with up to 90% mortality rates. In the 2014–2016 West Africa Ebola epidemic, there are 15,261 laboratory confirmed cases and 11,325 total deaths. The lack of effective vaccines and medicines for the prevention and treatment of filovirus infection in humans stresses the urgency to develop antiviral therapeutics against filovirus-associated diseases. Our previous study identified a histamine receptor antagonist compound CP19 as an Entry inhibitor against both EBOV and MARV. The preliminary structure-activity relationship (SAR) studies of CP19 showed that its piperidine, coumarin and linker were related with its antiviral activities. In this study, we performed detailed SAR studies on these groups with synthesized CP19 derivatives. We discovered that 1) the piperidine group could be optimized with heterocycles, 2) the substitution groups of C3 and C4 of coumarin should be relatively large hydrophobic groups and 3) the linker part should be least substituted. Based on the SAR analysis, we synthesized compound 32 as a potent Entry inhibitor of EBOV and MARV (IC50 = 0.5 μM for EBOV and 1.5 μM for MARV). The mutation studies of Ebola glycoprotein and molecular docking studies showed that the coumarin and its substituted groups of compound 32 bind to the pocket of Ebola glycoprotein in a similar way to the published Entry inhibitor compound 118a. However, the carboxamide group of compound 32 does not have strong interaction with N61 as compound 118a does. The coumarin skeleton structure and the binding model of compound 32 elucidated by this study could be utilized to guide further design and optimization of Entry Inhibitors targeting the filovirus glycoproteins.
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Identification of Diaryl-Quinoline Compounds as Entry Inhibitors of Ebola Virus.
Viruses, 2018Co-Authors: Qinghua Cui, Han Cheng, Rui Xiong, Gang Zhang, Manu Anantpadma, Robert A. Davey, Lijun RongAbstract:Ebola virus is the causative agent of Ebola virus disease in humans. The lethality of Ebola virus infection is about 50%, supporting the urgent need to develop anti-Ebola drugs. Glycoprotein (GP) is the only surface protein of the Ebola virus, which is functionally critical for the virus to attach and enter the host cells, and is a promising target for anti-Ebola virus drug development. In this study, using the recombinant HIV-1/Ebola pseudovirus platform we previously established, we evaluated a small molecule library containing various quinoline compounds for anti-Ebola virus Entry Inhibitors. Some of the quinoline compounds specifically inhibited the Entry of the Ebola virus. Among them, compound SYL1712 was the most potent Ebola virus Entry inhibitor with an IC50 of ~1 μM. The binding of SYL1712 to the vial glycoprotein was computationally modeled and was predicted to interact with specific residues of GP. We used the time of the addition assay to show that compound SYL1712 blocks Ebola GP-mediated Entry. Finally, consistent with being an Ebola virus Entry inhibitor, compound SYL1712 inhibited infectious Ebola virus replication in tissue culture under biosafety level 4 containment, with an IC50 of 2 μM. In conclusion, we identified several related molecules with a diaryl-quinoline scaffold as potential anti-EBOV Entry Inhibitors, which can be further optimized for anti-Ebola drug development.
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A cell‐based high‐throughput protocol to screen Entry Inhibitors of highly pathogenic viruses with Traditional Chinese Medicines
Journal of medical virology, 2016Co-Authors: Yong Yang, Han Cheng, Hui Yan, Peng Zhan Wang, Rong Rong, Yingying Zhang, Cheng Bo Zhang, Lijun RongAbstract:Emerging viruses such as Ebola virus (EBOV), Lassa virus (LASV), and avian influenza virus H5N1 (AIV) are global health concerns. Since there is very limited options (either vaccine or specific therapy) approved for humans against these viruses, there is an urgent need to develop prophylactic and therapeutic treatments. Previously we reported a high-throughput screening (HTS) protocol to identify Entry Inhibitors for three highly pathogenic viruses (EBOV, LASV, and AIV) using a human immunodeficiency virus-based pseudotyping platform which allows us to perform the screening in a BSL-2 facility. In this report, we have adopted this screening protocol to evaluate traditional Chinese Medicines (TCMs) in an effort to discover Entry Inhibitors against these viruses. Here we show that extracts of the following Chinese medicinal herbs exhibit potent anti-Ebola viral activities: Gardenia jasminoides Ellis, Citrus aurantium L., Viola yedoensis Makino, Prunella vulgaris L., Coix lacryma-jobi L. var. mayuen (Roman.) Stapf, Pinellia ternata (Thunb.) Breit., and Morus alba L. This study represents a proof-of-principle investigation supporting the suitability of this assay for rapid screening TCMs and identifying putative Entry Inhibitors for these viruses. J. Med. Virol. 89:908-916, 2017. © 2016 Wiley Periodicals, Inc.
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A Comparative High-Throughput Screening Protocol to Identify Entry Inhibitors of Enveloped Viruses
Journal of biomolecular screening, 2013Co-Authors: Juan Wang, Han Cheng, Kiira Ratia, Elizabeth Varhegyi, William Hendrickson, Lijun RongAbstract:Emerging and reemerging human viral pathogens pose great public health concerns since therapeutics against these viruses are limited. Thus, there is an urgent need to develop novel drugs that can block infection of either a specific virus or a number of viruses. Viral Entry is thought to be an ideal target for potential therapeutic prevention. One of the challenges of developing antivirals is that most of these viruses are highly pathogenic and therefore require high biosafety-level containment. In this study, we have adopted a comparative high-throughput screening protocol to identify Entry Inhibitors for three enveloped viruses (Marburg virus, influenza virus H5N1, and Lassa virus) using a human immunodeficiency virus-based pseudotyping platform. We demonstrate the utility of this approach by screening a small compound library and identifying putative Entry Inhibitors for these viruses. One major advantage of this protocol is to reduce the number of false positives in hit selection, and we believe that the protocol is useful for inhibitor screening for many enveloped viruses.
Richard K Plemper - One of the best experts on this subject based on the ideXlab platform.
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cross resistance mechanism of respiratory syncytial virus against structurally diverse Entry Inhibitors
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Vidhi D Thakkar, Martin L Moore, Richard K PlemperAbstract:Respiratory syncytial virus (RSV) is a leading pediatric pathogen that is responsible for a majority of infant hospitalizations due to viral disease. Despite its clinical importance, no vaccine prophylaxis against RSV disease or effective antiviral therapeutic is available. In this study, we established a robust high-throughput drug screening protocol by using a recombinant RSV reporter virus to expand the pool of RSV inhibitor candidates. Mechanistic characterization revealed that a potent newly identified inhibitor class blocks viral Entry through specific targeting of the RSV fusion (F) protein. Resistance against this class was induced and revealed overlapping hotspots with diverse, previously identified RSV Entry blockers at different stages of preclinical and clinical development. A structural and biochemical assessment of the mechanism of unique, broad RSV cross-resistance against structurally distinct Entry Inhibitors demonstrated that individual escape hotspots are located in immediate physical proximity in the metastable conformation of RSV F and that the resistance mutations lower the barrier for prefusion F triggering, resulting in an accelerated RSV Entry kinetics. One resistant RSV recombinant remained fully pathogenic in a mouse model of RSV infection. By identifying molecular determinants governing the RSV Entry machinery, this study spotlights a molecular mechanism of broad RSV resistance against Entry inhibition that may affect the impact of diverse viral Entry Inhibitors presently considered for clinical use and outlines a proactive design for future RSV drug discovery campaigns.
Kazuhisa Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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soluble type small molecule cd4 mimics as hiv Entry Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2019Co-Authors: Takuya Kobayakawa, Kazuhisa Yoshimura, Kiju Konno, Nami Ohashi, Kohei Takahashi, Ami Masuda, Shigeyoshi Harada, Hirokazu TamamuraAbstract:Abstract Several small molecule CD4 mimics have been reported previously as HIV-1 Entry Inhibitors, which block the interaction between the Phe43 cavity of HIV-1 gp120 and the host CD4. Known CD4 mimics such as NBD-556 possess significant anti-HIV activity but are less soluble in water, perhaps due to their hydrophobic aromatic ring-containing structures. Compounds with a pyridinyl group in place of the phenyl group in these molecules have been designed and synthesized in an attempt to increase the hydrophilicity. Some of these new CD4 mimics, containing a tetramethylpiperidine ring show significantly higher water solubility than NBD-556 and have high anti-HIV activity and synergistic anti-HIV activity with a neutralizing antibody. The CD4 mimic that has a cyclohexylpiperidine ring and a 6-fluoropyridin-3-yl ring has high anti-HIV activity and no significant cytotoxicity. The present results will be useful in the future design and development of novel soluble-type molecule CD4 mimics.
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small molecule cd4 mimics containing mono cyclohexyl moieties as hiv Entry Inhibitors
ChemMedChem, 2016Co-Authors: Nami Ohashi, Shigeyoshi Harada, Wataru Nomura, Takaaki Mizuguchi, Yu Irahara, Yuko Yamada, Misato Kotani, Shuzo Matsushita, Kazuhisa YoshimuraAbstract:CD4 mimics are small molecules that inhibit the protein-protein interaction between gp120 and CD4, which is a key interaction for the Entry of human immunodeficiency virus (HIV) into host immune cells. In the present study, mono-cyclohexyl-type CD4 mimics were designed to form hydrophobic and electrostatic interactions with Val430 and Asp368 located in the entrance of the Phe43 cavity of gp120, the interaction site of CD4. YIR-329, a novel 1-azaspiro[5.5]undecane derivative with a cyclohexyl ring attached to the piperidine ring, exhibited only slightly weaker anti-HIV activity than a previously described lead HAR-171, and modeling results indicated the formation of advantageous interactions by the para-chlorophenyl moiety of YIR-329. To introduce an electrostatic interaction with Asp368, derivatives with a guanidino group on the piperidine nitrogen atom were synthesized. Mono-cyclohexyl-type CD4 mimics with a guanidino group, such as YIR-819 (N(1) -(4-chlorophenyl)-N(2) -(1-(2-(N-(amidino)glycinamide)ethyl)-2-cyclohexylpiperidin-4-yl)oxalamide) and YIR-821 (1-(2-(5-guanidinovaleramide)ethyl derivative of YIR-819), were identified that exhibit approximately fivefold more potent anti-HIV activity than YIR-329. In combination with a neutralizing antibody, their anti-HIV activities were augmenting. Modeling results suggest that these compounds interact effectively with Val430 and either Asp368 or Asp474 in the gp120 Phe43 cavity. YIR-819 and YIR-821 represent useful lead compounds for the further development of HIV-1 Entry Inhibitors and could potentially be useful for co-administration with neutralizing antibodies for the treatment of HIV infection and AIDS.
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cd4 mimics as hiv Entry Inhibitors lead optimization studies of the aromatic substituents
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Tetsuo Narumi, Kazuhisa Yoshimura, Nami Ohashi, Shigeyoshi Harada, Hiroshi Arai, Yuki Hirota, Chie Hashimoto, Wataru NomuraAbstract:Several CD4 mimics have been reported as HIV-1 Entry Inhibitors that can intervene in the interaction between a viral envelope glycoprotein gp120 and a cell surface protein CD4. Our previous SAR studies led to a finding of a highly potent analogue 3 with bulky hydrophobic groups on a piperidine moiety. In the present study, the aromatic ring of 3 was modified systematically in an attempt to improve its antiviral activity and CD4 mimicry which induces the conformational changes in gp120 that can render the envelope more sensitive to neutralizing antibodies. Biological assays of the synthetic compounds revealed that the introduction of a fluorine group as a meta-substituent of the aromatic ring caused an increase of anti-HIV activity and an enhancement of a CD4 mimicry, and led to a novel compound 13a that showed twice as potent anti-HIV activity compared to 3 and a substantial increase in a CD4 mimicry even at lower concentrations.
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In vitro and In vivo Resistance to Human Immuno Deficiency Virus Type 1 Entry Inhibitors
Journal of AIDS and Clinical Research, 2012Co-Authors: Yosuke Maeda, Kazuhisa Yoshimura, Fusako Miyamoto, Eiichi N. Kodama, Harada Shigeyoshi, Yuzhe Yuan, Shinji Harada, Keisuke YusaAbstract:Viral Entry is one of the most important targets for the efficient treatment of Human immunodeficiency virus type 1 (HIV-1)-infected patients. The Entry process consists of multiple molecular steps: attachment of viral gp120 to CD4, interaction of gp120 with CCR5 or CXCR4 co-receptors, and gp41-mediated fusion of the viral and cellular membranes. Understanding the sequential steps of the Entry process has enabled the production of various antiviral drugs to block each of these steps. Currently, the CCR5 inhibitor, maraviroc, and the fusion inhibitor, enfuvirtide, are clinically available. However, the emergence of HIV-1 strains resistant to Entry Inhibitors, as commonly observed for other classes of antiviral agents, is a serious problem. In this review, we describe a variety of Entry Inhibitors targeting different steps of viral Entry and escape variants that are generated in vitro and in vivo.