@abrahamlabhms.bsky.social
Thank you, Blair!!!
December 30, 2025 at 6:32 PM
Thank you, Blair!!!
Thank you to everyone involved, including @joeloparo.bsky.social @kranzuschlab.bsky.social !
December 29, 2025 at 8:34 PM
Thank you to everyone involved, including @joeloparo.bsky.social @kranzuschlab.bsky.social !
HPIs provide a promising new approach to combatting herpesvirus drug resistance. Our study elucidates their inhibition mechanisms and offers insight into herpesvirus replisome assembly, providing a basis for further inhibitor development 💊
December 29, 2025 at 8:34 PM
HPIs provide a promising new approach to combatting herpesvirus drug resistance. Our study elucidates their inhibition mechanisms and offers insight into herpesvirus replisome assembly, providing a basis for further inhibitor development 💊
We also show that helicase residue K356 plays a key role in stabilizing HPI binding to the HSV-1 H/P complex. UL52 residues used in drug binding are poorly conserved across β- and γ-herpesviruses, a possible explanation for α-herpesvirus drug specificity.
December 29, 2025 at 8:34 PM
We also show that helicase residue K356 plays a key role in stabilizing HPI binding to the HSV-1 H/P complex. UL52 residues used in drug binding are poorly conserved across β- and γ-herpesviruses, a possible explanation for α-herpesvirus drug specificity.
Using optical tweezers experiments with @JoeLoparo lab, we show that HPIs block DNA translocation such that the complex pauses on DNA. Structural analysis reveals that HPIs lock 🔒the UL5 helicase in an open conformation, preventing motor domains from closing.
December 29, 2025 at 8:34 PM
Using optical tweezers experiments with @JoeLoparo lab, we show that HPIs block DNA translocation such that the complex pauses on DNA. Structural analysis reveals that HPIs lock 🔒the UL5 helicase in an open conformation, preventing motor domains from closing.
We discovered an extensive interface between polymerase (UL30) and helicase (UL5), mediated in part by a conserved motif within the polymerase.
December 29, 2025 at 8:34 PM
We discovered an extensive interface between polymerase (UL30) and helicase (UL5), mediated in part by a conserved motif within the polymerase.
Cryo-EM maps of H/P subunits UL5, UL52, and UL8 reveal a bilobed architecture centered on primase UL52. Further addition of the polymerase holoenzyme UL30 and UL42 allowed us to understand how the HSV-1 replication fork assembles onto DNA and its inhibition by HPI drugs.
December 29, 2025 at 8:34 PM
Cryo-EM maps of H/P subunits UL5, UL52, and UL8 reveal a bilobed architecture centered on primase UL52. Further addition of the polymerase holoenzyme UL30 and UL42 allowed us to understand how the HSV-1 replication fork assembles onto DNA and its inhibition by HPI drugs.
The HSV helicase-primase (H/P) complex–involved in viral genome replication–is a promising target for emerging drugs, known as helicase-primase inhibitors (HPIs) 💊 Our recent @CellCellPress paper uses cryo-EM to reveal mechanisms behind why these new drugs are effective.
December 29, 2025 at 8:34 PM
The HSV helicase-primase (H/P) complex–involved in viral genome replication–is a promising target for emerging drugs, known as helicase-primase inhibitors (HPIs) 💊 Our recent @CellCellPress paper uses cryo-EM to reveal mechanisms behind why these new drugs are effective.
Herpesviruses are prevalent pathogens, with HSV-1 causing orolabial infections and severe disease in immunocompromised patients 😷Because of the risk HSV-1 developing resistance to current drugs, new antiviral strategies are a priority.
December 29, 2025 at 8:34 PM
Herpesviruses are prevalent pathogens, with HSV-1 causing orolabial infections and severe disease in immunocompromised patients 😷Because of the risk HSV-1 developing resistance to current drugs, new antiviral strategies are a priority.
Though the Candid#1 vaccine is effective against JUNV, other lethal New World arenaviruses still pose a large public health risk 🌎with no specific medical countermeasures. The structures may serve as a basis for further rational design and development of therapeutics and vaccines
August 9, 2025 at 9:51 AM
Though the Candid#1 vaccine is effective against JUNV, other lethal New World arenaviruses still pose a large public health risk 🌎with no specific medical countermeasures. The structures may serve as a basis for further rational design and development of therapeutics and vaccines
A K33A substitution in the stable signal peptide (SSP) allowed for stabilization of the pre-fusion GPC, with molecular dynamics suggesting K33A stabilizes GPC by better accommodating membrane lipids in the SSP33 pocket, supported by our cryo-EM density
August 9, 2025 at 9:51 AM
A K33A substitution in the stable signal peptide (SSP) allowed for stabilization of the pre-fusion GPC, with molecular dynamics suggesting K33A stabilizes GPC by better accommodating membrane lipids in the SSP33 pocket, supported by our cryo-EM density
Further structural and functional analyses also reveal the effect of specific residues in transmembrane and membrane proximal region on pH-mediated fusion, elucidating the attenuation mechanism of the JUNV Candid#1 vaccine
August 9, 2025 at 9:51 AM
Further structural and functional analyses also reveal the effect of specific residues in transmembrane and membrane proximal region on pH-mediated fusion, elucidating the attenuation mechanism of the JUNV Candid#1 vaccine
These cryo-EM structures reveal notable differences between JUNV and MACV in GP1 organization at the apex and C terminus. The MACV GPC apex has a more open appearance due to its GP1 subunits slightly rotating outwards and clockwise 🔃compared to JUNV GP1 subunits
August 9, 2025 at 9:51 AM
These cryo-EM structures reveal notable differences between JUNV and MACV in GP1 organization at the apex and C terminus. The MACV GPC apex has a more open appearance due to its GP1 subunits slightly rotating outwards and clockwise 🔃compared to JUNV GP1 subunits
Our @natmicrobiol.nature.com paper provides the most complete insight into the molecular organization of the JUNV and MACV GPCs yet 😲revealing new features not seen in previous structures, such as the TM helices and cytosolic portions, including ZBD
August 9, 2025 at 9:51 AM
Our @natmicrobiol.nature.com paper provides the most complete insight into the molecular organization of the JUNV and MACV GPCs yet 😲revealing new features not seen in previous structures, such as the TM helices and cytosolic portions, including ZBD
New World arenaviruses, like Junin virus (JUNV) and Machupo virus (MACV), cause hemorrhagic fever with fatality rates as high as 30% predominantly in South America. To date, the only medical countermeasure against these viruses is the Candid#1 vaccine effective only against JUNV
August 9, 2025 at 9:51 AM
New World arenaviruses, like Junin virus (JUNV) and Machupo virus (MACV), cause hemorrhagic fever with fatality rates as high as 30% predominantly in South America. To date, the only medical countermeasure against these viruses is the Candid#1 vaccine effective only against JUNV
WEEV re-emerged in South America in 2023-2024 in a large outbreak, highlighting the critical need for preparedness. Using the structures, we identified E2 polymorphisms that predict WEEV strain receptor dependency, which will support environmental surveillance.
April 4, 2025 at 7:59 PM
WEEV re-emerged in South America in 2023-2024 in a large outbreak, highlighting the critical need for preparedness. Using the structures, we identified E2 polymorphisms that predict WEEV strain receptor dependency, which will support environmental surveillance.
Interesting tidbit in the story: a WEEV-related alphavirus that circulates on the east coast (EEEV territory) called highlands J virus (HJV) also uses PCDH10 as a receptor. It diverged from WEEV not that long ago and retained most PCDH10 contact residues.
April 4, 2025 at 7:59 PM
Interesting tidbit in the story: a WEEV-related alphavirus that circulates on the east coast (EEEV territory) called highlands J virus (HJV) also uses PCDH10 as a receptor. It diverged from WEEV not that long ago and retained most PCDH10 contact residues.
Some WEEV strains and EEEV both bind VLDLR at the LA1 and LA2 domains, suggesting that VLDLR LA1-LA2 decoy receptor may have broad activity against them. This molecule protected mice against lethal challenge by a WEEV strain that binds VLDLR.
April 4, 2025 at 7:59 PM
Some WEEV strains and EEEV both bind VLDLR at the LA1 and LA2 domains, suggesting that VLDLR LA1-LA2 decoy receptor may have broad activity against them. This molecule protected mice against lethal challenge by a WEEV strain that binds VLDLR.
Strains isolated during epidemics of the early 20th century bind VLDLR and ApoER2 as additional receptors. Our structure of a 1941 strain bound by VLDLR revealed a distinct binding mode than other alphaviruses that bind LDLR-related proteins, such as EEEV, SFV or VEEV.
April 4, 2025 at 7:59 PM
Strains isolated during epidemics of the early 20th century bind VLDLR and ApoER2 as additional receptors. Our structure of a 1941 strain bound by VLDLR revealed a distinct binding mode than other alphaviruses that bind LDLR-related proteins, such as EEEV, SFV or VEEV.