Abstract
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.
Highlights
According to UNAIDS, approximately 36.9 million people worldwide were living with human immunodeficiency virus (HIV) in 2017
We found that all these combinations exhibited synergistic anti-HIV-1 activity against infection by laboratory-adapted and primary HIV-1 strains, including those resistant to NRTIs and peptide-based HIV-1 entry inhibitors [60]
C60 inhibits the activity of HIV-1 infection at low μM levels, it can be used as a probe to study the membrane fusion mechanism of HIV-1 and as a lead to develop HIV entry inhibitors targeting 6HB
Summary
According to UNAIDS, approximately 36.9 million people worldwide were living with human immunodeficiency virus (HIV) in 2017 (https://www.unaids.org). A variety of substances work cooperatively and synergistically during viral-cell membrane fusion and create complex interactive networks involving a variety of protein-protein interactions, such as CD4-gp120 [3,4,5], gp120-CCR5 / CXCR4 [6], gp120-gp41 [7,8], gp NHR-CHR [9], and interaction between the intracellular and extracellular regions of gp41 [10] Entry inhibitors target these proteins, their interfaces, or other sites to block viral invasion and can be divided into three major subclasses: adhesion inhibitors, targeting CD4 or gp120 to block CD4-gp120 interaction; coreceptor inhibitors, targeting CCR5 or CXCR4 to inhibit the binding of gp120 to the coreceptor; and fusion inhibitors, targeting gp to interfere with its conformational change required for viral fusion and entry. We will discuss the characteristics of protein- and peptide-based inhibitors that target HIV Env and look ahead to their development
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