Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances - including the development of direct electron detectors and more effective computational image analysis techniques - are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies. These advances have raised hopes that single-particle cryo-EM might soon become an important tool for drug discovery, particularly if they could enable structural determination for 'intractable' targets that are still not accessible to X-ray crystallographic analysis. This article describes the recent advances in the field and critically assesses their relevance for drug discovery as well as discussing at what stages of the drug discovery pipeline cryo-EM can be useful today and what to expect in the near future.

Cryo-EM in drug discovery: achievements, limitations and prospects

Targeting the Latent Reservoir for HIV-1

HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure.

https://www.cell.com/trends/microbiology/pdf/S0966-842X(19)30157-X.pdf

Molecular Mechanism of HIV-1 Entry.

Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization

Cryo-EM analyses of the initial contact of the HIV-1 Env trimer with the CD4 receptor reveal that CD4 interacts with two gp120 protomers; these quaternary contacts are important for viral infectivity. Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-A resolution. A single CD4 molecule is embraced by a quaternary HIV-1–Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurred after the mutation of CD4 residues that interact with CD4-BS2. Our results document the critical role of quaternary interactions in the initial HIV-Env-receptor contact, with implications for treatment and vaccine design.

/pdf/quaternary-contact-in-the-initial-interaction-of-cd4-with-ihc119p9i8.pdf

Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer.

The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4+ T cell depletion. Accordingly, in vivo treatment with an antibody to the gut-homing integrin α4β7 was shown to reduce viral transmission, delay disease progression, and induce persistent virus control in macaques challenged with simian immunodeficiency virus (SIV). We show that integrin α4β7 is efficiently incorporated into the envelope of HIV-1 virions. Incorporated α4β7 is functionally active as it binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1), promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediate trans-infection of bystander cells. Functional α4β7 is present in circulating virions from HIV-infected patients and SIV-infected macaques, with peak levels during the early stages of infection. In vivo homing experiments documented selective and specific uptake of α4β7+ HIV-1 virions by high endothelial venules in the intestinal mucosa. These results extend the paradigm of tissue homing to a retrovirus and are relevant for the pathogenesis, treatment, and prevention of HIV-1 infection.

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

Nat. Struct. Mol. Biol. 24, 370–378 (2017); published online 20 February 2017; corrected after print 27 April 2017 In the version of this article initially published, funding information for B.C. and C.S.P. was missing NIH grant S10 OD019994-01. In addition, there was an incorrect comma in the introduction (after “glycoprotein” in the sentence “Upon binding to the primary cellular receptor, CD4, the external gp120 Env glycoprotein undergoes major conformational changes.

/pdf/corrigendum-quaternary-contact-in-the-initial-interaction-of-39duqot4b7.pdf

Corrigendum: Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer.

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Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer.

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

Corrigendum: Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer.