3 research outputs found
Convergent evolution in the mechanisms of ACBD3 recruitment to picornavirus replication sites
Author summary Enteroviruses are the most common viruses infecting humans. They cause a broad spectrum of diseases ranging from common cold to life-threatening diseases, such as poliomyelitis. To date, no effective antiviral therapy for enteroviruses has been approved yet. To ensure efficient replication, enteroviruses hijack several host factors, recruit them to the sites of virus replication, and use their physiological functions for their own purposes. Here, we characterize the complexes composed of the host protein ACBD3 and the ACBD3-binding viral proteins (called 3A) of four representative enteroviruses. Our study reveals the atomic details of these complexes and identifies the amino acid residues important for the interaction. We found out that the 3A proteins of enteroviruses bind to the same regions of ACBD3 as the 3A proteins of kobuviruses, a distinct group of viruses that also rely on ACBD3, but are oriented in the opposite directions. This observation reveals a striking case of convergent evolutionary pathways that have evolved to allow enteroviruses and kobuviruses (which are two distinct groups of the Picornaviridae family) to recruit a common host target, ACBD3, and its downstream effectors to the sites of viral replication
Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7‑Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists
Cyclic dinucleotides (CDNs) are second messengers that
activate
stimulator of interferon genes (STING). The cGAS-STING pathway plays
a promising role in cancer immunotherapy. Here, we describe the synthesis
of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse
cyclic GMP–AMP synthase and bacterial dinucleotide synthases
for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine
CDNs were prepared by Suzuki–Miyaura cross-couplings. New CDNs
were tested in biochemical and cell-based assays for their affinity
to human STING. Eight CDNs showed better activity than 2′3′-cGAMP, the natural ligand of STING. The effect on cytokine
and chemokine induction was also evaluated. The best activities were
observed for CDNs bearing large aromatic substituents that point above
the CDN molecule. We solved four X-ray structures of complexes of
new CDNs with human STING. We observed π–π stacking
interactions between the aromatic substituents and Tyr240 that are
involved in the stabilization of CDN-STING complexes
Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7‑Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists
Cyclic dinucleotides (CDNs) are second messengers that
activate
stimulator of interferon genes (STING). The cGAS-STING pathway plays
a promising role in cancer immunotherapy. Here, we describe the synthesis
of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse
cyclic GMP–AMP synthase and bacterial dinucleotide synthases
for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine
CDNs were prepared by Suzuki–Miyaura cross-couplings. New CDNs
were tested in biochemical and cell-based assays for their affinity
to human STING. Eight CDNs showed better activity than 2′3′-cGAMP, the natural ligand of STING. The effect on cytokine
and chemokine induction was also evaluated. The best activities were
observed for CDNs bearing large aromatic substituents that point above
the CDN molecule. We solved four X-ray structures of complexes of
new CDNs with human STING. We observed π–π stacking
interactions between the aromatic substituents and Tyr240 that are
involved in the stabilization of CDN-STING complexes