Small Molecule Inhibitors of Influenza Virus Entry

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

Download Full-text

CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

Open Biology ◽

10.1098/rsob.130217 ◽

2014 ◽

Vol 4 (2) ◽

pp. 130217 ◽

Cited By ~ 36

Author(s):

Puneet Sharma ◽

Alo Nag

Keyword(s):

Ubiquitin Ligase ◽

Drug Target ◽

Critical Role ◽

Cellular Transformation ◽

Biological Processes ◽

Molecular Architecture ◽

The Past ◽

Cullin 4A ◽

Broad Overview

The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.

Download Full-text

Optimization of Small-Molecule Inhibitors of Influenza Virus Polymerase: From Thiophene-3-Carboxamide to Polyamido Scaffolds

Journal of Medicinal Chemistry ◽

10.1021/jm500300r ◽

2014 ◽

Vol 57 (10) ◽

pp. 4337-4350 ◽

Cited By ~ 39

Author(s):

Susan Lepri ◽

Giulio Nannetti ◽

Giulia Muratore ◽

Gabriele Cruciani ◽

Renzo Ruzziconi ◽

...

Keyword(s):

Influenza Virus ◽

Small Molecule ◽

Small Molecule Inhibitors

Download Full-text

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.

Download Full-text

Phenotypic Screening of Small-Molecule Inhibitors: Implications for Therapeutic Discovery and Drug Target Development in Traumatic Brain Injury

Methods in Molecular Biology - Injury Models of the Central Nervous System ◽

10.1007/978-1-4939-3816-2_37 ◽

2016 ◽

pp. 677-688 ◽

Cited By ~ 1

Author(s):

Hassan Al-Ali ◽

Vance P. Lemmon ◽

John L. Bixby

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Small Molecule ◽

Drug Target ◽

Small Molecule Inhibitors ◽

Phenotypic Screening

Download Full-text

A Primary Evaluation of Potential Small‐Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment

ChemMedChem ◽

10.1002/cmdc.202000397 ◽

2020 ◽

Vol 15 (16) ◽

pp. 1499-1504 ◽

Cited By ~ 1

Author(s):

Hagen Körschgen ◽

Christian Jäger ◽

Kathrin Tan ◽

Mirko Buchholz ◽

Walter Stöcker ◽

...

Keyword(s):

Small Molecule ◽

Drug Target ◽

Small Molecule Inhibitors ◽

Infertility Treatment ◽

Female Infertility ◽

Primary Evaluation ◽

Novel Drug

Download Full-text

A Novel Platelet Small-Molecule Agonist Targeting Glycoprotein Ibalpha.

Blood ◽

10.1182/blood.v114.22.4010.4010 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4010-4010

Author(s):

Jianfeng Yang ◽

Zhi Chen ◽

Weiliang Zhu ◽

Changgeng Ruan

Keyword(s):

Monoclonal Antibody ◽

Platelet Aggregation ◽

Small Molecule ◽

Platelet Adhesion ◽

Conflicts Of Interest ◽

Critical Role ◽

Structural Basis ◽

Terminal Fragment ◽

Von Willebrand

Abstract Abstract 4010 Poster Board III-946 Introduction Interaction of glycoprotein (GP) Ibα with Von Willebrand factor (VWF) plays a critical role in platelet adhesion and signal transduction for αIIbβ3 activation under condition of high shear stress. Methods Based on the crystal structure of platelet GPIbα (PDB:1P9A), virtual screening was employed to identify active compounds. Compounds in SPECS database were docked to VWF binding site on the surface of GPIbα. The screening was carried out with the DOCK4.0 program. The 150 highest-scoring compounds were obtained for further bioassay and those with inhibitory activity of VWF binding to GPIbα were investigated the effect on platelet activation and aggregation. Results We found one compound, designated it as YC148, blocked ristocetin-induced plasma VWF binding to recombinant N-terminal fragment GPIbα (H1-V289) by ELISA method. More interestingly, YC148 did not inhibit ristocetin-induced platelet aggregation, on the contrary, it induced platelet aggregation itself in the absence of exogenous modulators such as ristocetin and botrocetin. A VWF A1 blocking antibody could not block platelet aggregation induced by YC148 despite it completely inhibited ristocetin-induced platelet agglutination. And YC148 also stimulated washed platelet aggregation where VWF was absent in the resuspension buffer. These indicated that the aggregation stimulated by YC148 could not the result from VWF binding. Flow cytomety also showed that YC148 increased P-selectin expression on platelet membrane and promoted monoclonal antibody PAC-1 binding to platelet. The platelet aggregation stimulated by YC148 was inhibited by anti-GPIbα monoclonal antibody AN51 and 6D1. Conclusion A novel exogenous small-molecule agonist was found to activate platelet through binding to GPIbα. It provides us a new tool for investigating platelet GPIb outside-in signaling pathway in platelet adhesion and aggregation. Furthermore, the structure of YC148 may provide a structural basis for developing new hemostatic drugs based on the inhibition of VWF-GPIb interaction. The effect of YC148 on platelet from Bernard-Soulier syndrome or GPIbα N-terminal fragment deficient platelet after in vitro cleavage will be further investigated. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Acid phosphatase 2 (ACP2) is required for membrane fusion during influenza virus entry

Scientific Reports ◽

10.1038/srep43893 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Jihye Lee ◽

Jinhee Kim ◽

Kidong Son ◽

Anne-Laure Pham Humg d’Alexandry d’Orengiani ◽

Ji-Young Min

Keyword(s):

Influenza Virus ◽

Acid Phosphatase ◽

Membrane Fusion ◽

Virus Entry

Download Full-text

Viral Membrane Fusion and the Transmembrane Domain

Viruses ◽

10.3390/v12070693 ◽

2020 ◽

Vol 12 (7) ◽

pp. 693 ◽

Cited By ~ 1

Author(s):

Chelsea T. Barrett ◽

Rebecca Ellis Dutch

Keyword(s):

Membrane Fusion ◽

Host Cell ◽

Fusion Proteins ◽

Transmembrane Domain ◽

Critical Role ◽

Viral Fusion ◽

Transmembrane Region ◽

Host Cell Membrane ◽

The Past ◽

Viral Fusion Proteins

Initiation of host cell infection by an enveloped virus requires a viral-to-host cell membrane fusion event. This event is mediated by at least one viral transmembrane glycoprotein, termed the fusion protein, which is a key therapeutic target. Viral fusion proteins have been studied for decades, and numerous critical insights into their function have been elucidated. However, the transmembrane region remains one of the most poorly understood facets of these proteins. In the past ten years, the field has made significant advances in understanding the role of the membrane-spanning region of viral fusion proteins. We summarize developments made in the past decade that have contributed to the understanding of the transmembrane region of viral fusion proteins, highlighting not only their critical role in the membrane fusion process, but further demonstrating their involvement in several aspects of the viral lifecycle.

Download Full-text

Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics

Molecules ◽

10.3390/molecules23112757 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2757 ◽

Cited By ~ 7

Author(s):

Chiranjeev Sharma ◽

Young Seo

Keyword(s):

Small Molecule ◽

Drug Target ◽

Small Molecule Inhibitors ◽

Chemotherapeutic Agents ◽

Heat Shock Factor 1 ◽

Next Generation ◽

Anticancer Activities ◽

Cancer Cell Growth ◽

Survival Studies ◽

New Chemotherapeutic Agents

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

Download Full-text