Structure-Based Design, Synthesis and Validation of CD4-Mimetic Small Molecule Inhibitors of HIV-1 Entry: Conversion of a Viral Entry Agonist to an Antagonist

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

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Design, Synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116000 ◽

2021 ◽

pp. 116000

Author(s):

Francesca Curreli ◽

Shahad Ahmed ◽

Sofia M. Benedict Victor ◽

Ildar R. Iusupov ◽

Evgeny A. Spiridonov ◽

...

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Design Synthesis ◽

Entry Inhibitors ◽

Hiv 1

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Interaction of small molecule inhibitors of HIV-1 entry with CCR5

Virology ◽

10.1016/j.virol.2006.01.018 ◽

2006 ◽

Vol 349 (1) ◽

pp. 41-54 ◽

Cited By ~ 98

Author(s):

Christoph Seibert ◽

Weiwen Ying ◽

Svetlana Gavrilov ◽

Fotini Tsamis ◽

Shawn E. Kuhmann ◽

...

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

Hiv 1

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Small-Molecule Inhibitors of HIV-1 Protease Dimerization Derived from Cross-Linked Interfacial Peptides

Angewandte Chemie ◽

10.1002/1521-3757(20000804)112:15<2822::aid-ange2822>3.0.co;2-1 ◽

2000 ◽

Vol 112 (15) ◽

pp. 2822-2825 ◽

Cited By ~ 4

Author(s):

Michael D. Shultz ◽

Michael J. Bowman ◽

Young-Wan Ham ◽

Xuimin Zhao ◽

George Tora ◽

...

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

Hiv 1

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Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Cells ◽

10.3390/cells9081876 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1876

Author(s):

Magdalena Massalska ◽

Wlodzimierz Maslinski ◽

Marzena Ciechomska

Keyword(s):

Rheumatoid Arthritis ◽

Small Molecule ◽

Viral Entry ◽

Small Molecule Inhibitors ◽

Large Family ◽

Downstream Signaling ◽

Wide Range ◽

Synthetic Dmards ◽

Potential Strategy ◽

Inflammatory Molecules

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

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Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins

mBio ◽

10.1128/mbio.01598-16 ◽

2016 ◽

Vol 7 (5) ◽

Cited By ~ 59

Author(s):

Alon Herschhorn ◽

Xiaochu Ma ◽

Christopher Gu ◽

John D. Ventura ◽

Luis Castillo-Menendez ◽

...

Keyword(s):

Small Molecule ◽

Intermediate State ◽

Neutralizing Antibodies ◽

Small Molecule Inhibitors ◽

Virus Entry ◽

Envelope Glycoproteins ◽

Low Levels ◽

State 1 ◽

Hiv 1 ◽

Conformation State

ABSTRACTPrimary human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimers [(gp120/gp41)3] typically exist in a metastable closed conformation (state 1). Binding the CD4 receptor triggers Env to undergo extensive conformational changes to mediate virus entry. We identified specific gp120 residues that restrain Env in state 1. Alteration of these restraining residues destabilized state 1, allowing Env to populate a functional conformation (state 2) intermediate between state 1 and the full CD4-bound state (state 3). Increased state 2 occupancy was associated with lower energy barriers between the states. State 2 was an obligate intermediate for all transitions between state 1 and state 3. State 2-enriched Envs required lower CD4 concentrations to trigger virus entry and more efficiently infected cells expressing low levels of CD4. These Envs were resistant to several broadly neutralizing antibodies and small-molecule inhibitors. Thus, state 2 is an Env conformation on the virus entry pathway; sampling state 2 increases the adaptability of HIV-1 to different host cell receptor levels and immune environments. Our results provide new insights into the conformational regulation of HIV-1 entry.IMPORTANCEThe envelope glycoproteins (Env) of HIV-1 mediate virus entry and are the sole targets of neutralizing antibodies. Understanding the way that Env promotes HIV-1 entry can expedite drug and vaccine development. By destabilizing Env, we found that it assumes an intermediate state that is functional and obligate for transitions to entry-competent conformations. Increased sampling of this state enhances the ability of HIV-1 to infect cells that express low levels of the CD4 receptor and allows the virus to evade neutralizing antibodies and small-molecule inhibitors. These findings provide new mechanistic insights into the function and inhibition of HIV-1 Env and will contribute to ongoing therapeutic and prevention efforts to combat HIV-1.

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38 Small molecule inhibitors of BAF; a new family of compounds in HIV-1 latency reversal

Journal of Virus Eradication ◽

10.1016/s2055-6640(20)30983-3 ◽

2016 ◽

Vol 2 ◽

pp. 22

Author(s):

E. De Crignis ◽

M. Stoszko ◽

C. Rokx ◽

M.M. Khalid ◽

C. Lungu ◽

...

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

New Family ◽

Hiv 1

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Molecular docking and MM/GBSA integrated protocol for designing small molecule inhibitors against HIV-1 gp41

Medicinal Chemistry Research ◽

10.1007/s00044-014-1185-8 ◽

2014 ◽

Vol 24 (2) ◽

pp. 829-841 ◽

Cited By ~ 10

Author(s):

Ramakrishna Munnaluri ◽

Sree Kanth Sivan ◽

Vijjulatha Manga

Keyword(s):

Molecular Docking ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Hiv 1

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Pharmacophore-Based Discovery of Small-Molecule Inhibitors of Protein-Protein Interactions between HIV-1 Integrase and Cellular Cofactor LEDGF/p75

ChemMedChem ◽

10.1002/cmdc.200900070 ◽

2009 ◽

Vol 4 (8) ◽

pp. 1311-1316 ◽

Cited By ~ 74

Author(s):

Laura De Luca ◽

Maria Letizia Barreca ◽

Stefania Ferro ◽

Frauke Christ ◽

Nunzio Iraci ◽

...

Keyword(s):

Small Molecule ◽

Protein Interactions ◽

Small Molecule Inhibitors ◽

Protein Protein Interactions ◽

Cellular Cofactor ◽

Hiv 1

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Biochemical and Genetic Characterizations of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions

Journal of Virology ◽

10.1128/jvi.77.19.10528-10536.2003 ◽

2003 ◽

Vol 77 (19) ◽

pp. 10528-10536 ◽

Cited By ~ 112

Author(s):

Qi Guo ◽

Hsu-Tso Ho ◽

Ira Dicker ◽

Li Fan ◽

Nannan Zhou ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Small Molecule ◽

Viral Entry ◽

Binding Pocket ◽

Gp120 Protein ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.

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