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1.
Bioorg Med Chem ; 52: 116526, 2021 12 15.
Article in English | MEDLINE | ID: mdl-34839157

ABSTRACT

The HIV-1 invasion is initiated with the interaction of viral glycoprotein gp120 and cellular receptor CD4. The binding mechanism reveals two major hotspots involved in gp120-CD4 interaction. The first one is a hydrophobic cavity (Phe43 cavity) on gp120 capped with phenyl ring of phe43CD4 and the second is the electrostatic interaction between positive charge of Arg59CD4 and negative charge of Asp368gp120. Targeting these hotspots, small molecules for entry inhibition and HIV-1 neutralization were designed and tested. In the process, pyrimidine derivatives were identified as potent molecules to intercept gp120-CD4 binding by targeting both the hotspots. Herein, the synthesis, characterization of 1,2,3,4-Tetrahydropyrimidine derivatives, and biological evaluation on 93IN101, a clade C virus are presented. The paper presents a novel set of entry inhibitors to target dual hotspots on gp120 to inhibit protein-protein interactions.


Subject(s)
Anti-HIV Agents/pharmacology , Drug Design , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Pyrimidinones/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Dose-Response Relationship, Drug , HIV Envelope Protein gp120 , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/chemistry , HIV-1/metabolism , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity Relationship
2.
Bioorg Chem ; 116: 105313, 2021 11.
Article in English | MEDLINE | ID: mdl-34517280

ABSTRACT

The third variable loop region (V3 loop) on gp120 plays an important role in cellular entry of HIV-1. Its interaction with the cellular CD4 and coreceptors is an important hallmark in facilitating the bridging by gp41 and subsequent fusion of membranes for transfer of viral genetic material. Further, the virus phenotype determines the cell tropism via respective co- receptor binding. Thus, coreceptor binding motif of envelope is considered to be a potent anti-viral drug target for viral entry inhibition. However, its high variability in sequence is the major hurdle for developing inhibitors targeting the region. In this study, we have used an in silico Virtual Screening and "Fragment-based" method to design small molecules based on the gp120 V3 loop interactions with a potent broadly neutralizing human monoclonal antibody, 447-52D. From the in silico analysis a potent scaffold, 1,3,5-triazine was identified for further development. Derivatives of 1,3,5-triazine with specific functional groups were designed and synthesized keeping the interaction with co-receptor intact. Finally, preliminary evaluation of molecules for HIV-1 inhibition on two different virus strains (clade C, clade B) yielded IC50 < 5.0 µM. The approach used to design molecules based on broadly neutralizing antibody, was useful for development of target specific potent antiviral agents to prevent HIV entry. The study reported promising inhibitors that could be further developed and studied.


Subject(s)
Anti-HIV Agents/pharmacology , Broadly Neutralizing Antibodies/pharmacology , Drug Design , HIV Envelope Protein gp120/antagonists & inhibitors , HIV-1/drug effects , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Broadly Neutralizing Antibodies/chemistry , Dose-Response Relationship, Drug , HIV Envelope Protein gp120/metabolism , HIV-1/metabolism , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
3.
Colloids Surf B Biointerfaces ; 191: 110979, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32276212

ABSTRACT

Intriguing properties and structural dynamics of Lactoferrin have been exploited in numerous applications, including its use as self-assembling, pH sensitive nanoparticles to deliver intended cargo at the disease site. In this study, we explore the possibility of surface modification of Lactoferrin nanoparticles to hone its specificity to target HIV-1 infected cells. Existence of free cysteine groups on Lactoferrin nanoparticles available for reaction with external molecules facilitates conjugation on the surface with Sodium 2-mercaptoethanesulfonate (MES). Conjugation with MES is used to edge a negative charge that can mimic CCR5 and Heparan sulfate (initial point of contact of HIV-1 env to host cell surface) electrostatic charge (Sulfate group). A simple sono-chemical irradiation method was employed for self-assembly of Nanoparticles and for surface modification. The nanoparticles serve dual purpose to abrogate extracellular entry and to target viral enzymes, when loaded with ART drugs. The morphology and size distribution of the formed particles were explored using Transmission Electron Microscope (TEM), Scanning Electron Microscope (SEM) and Dynamic Light Scattering. Raman SERS was employed to understand the difference in the protein upon surface modification. The anti-HIV property of the particles was confirmed in-vitro. The modified device demonstrated acceptable nanoparticle properties with controlled release and higher effective concentration in the area of infection.


Subject(s)
Anti-Infective Agents/administration & dosage , Drug Carriers/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , Lactoferrin/administration & dosage , Nanoparticles/administration & dosage , Sulfonic Acids/chemistry , Anti-Infective Agents/chemistry , Cells, Cultured , HIV Envelope Protein gp160/metabolism , HIV Infections/metabolism , HIV Infections/virology , HIV-1/metabolism , Humans , Lactoferrin/chemistry , Nanoparticles/chemistry
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