The dawn of ven­ture cap­i­tal-backed cryo-EM star­tups

Last month, Septer­na, Inc., be­came the lat­est in a re­cent string of new biotechs to launch by build­ing on cryo-elec­tron mi­croscopy (cryo-EM) and oth­er trans­for­ma­tive plat­form tech­nolo­gies, to de­liv­er nov­el ther­a­peu­tics for new and well-val­i­dat­ed drug tar­gets alike. With fi­nanc­ing led by Third Rock Ven­tures, Septer­na, Inc., closed a $100M Se­ries A fi­nanc­ing round to lever­age its pro­pri­etary Na­tive Com­plex Plat­form for cryo-EM en­abled struc­ture-based drug de­sign, to tar­get na­tive G pro­tein-cou­pled re­cep­tors (GPCRs) with nov­el small mol­e­cule med­i­cines, cov­er­ing a wide range of ther­a­peu­tic ar­eas.

Like Septer­na, Inc., oth­er biotech­nol­o­gy com­pa­nies, such as MO­MA Ther­a­peu­tics, Gen­er­ate Bio­med­i­cines, and Gan­dee­va Ther­a­peu­tics, Inc., use cryo-EM as an es­sen­tial in­no­va­tion plat­form to dri­ve both tar­get val­i­da­tion and nov­el ther­a­peu­tic modal­i­ties. Cryo-EM al­so con­tributes to the suc­cess of re­lat­ed plat­form com­pa­nies, like So­sei Hep­tares, Con­fometRx Inc., and As­tex Phar­ma­ceu­ti­cals Inc., as well as nu­mer­ous big com­pa­nies that have in­te­grat­ed cryo-EM in­to their work­flows.¹

How the cryo-EM rev­o­lu­tion pro­pels struc­ture-based drug de­sign for dif­fi­cult tar­gets

The track record of GPCRs as the most suc­cess­ful drug tar­get class is well known. De­spite that suc­cess, the full po­ten­tial of this tar­get class re­mains un­tapped. Re­searchers from So­sei Hep­tares, a lead­ing GPCR struc­ture-based drug de­sign com­pa­ny, sug­gest that less than 13% of the po­ten­tial­ly use­ful ther­a­peu­tic modal­i­ties per­ti­nent to GPCRs have been suc­cess­ful to date.² The un­der-ex­ploita­tion of GPCRs is in no small part be­cause tar­get­ing GPCRs of­ten calls for high­ly re­cep­tor-se­lec­tive and tis­sue-spe­cif­ic drugs. In a re­cent sci­en­tif­ic ar­ti­cle, re­searchers from So­sei Hep­tares de­scribed how struc­ture-based drug de­sign could be used to dis­cov­er sub­type-spe­cif­ic mus­carinic re­cep­tor ag­o­nists that pri­mar­i­ly act in the brain.³ A  press re­lease lat­er an­nounced a $2.6 bil­lion deal with Neu­ro­crine Bio­sciences to clin­i­cal­ly ad­vance their se­lec­tive mus­carinic re­cep­tor ag­o­nist port­fo­lio for the treat­ment of neu­ropsy­chi­atric dis­or­ders. In oth­er words, struc­ture-based drug de­sign en­ables dis­cov­ery of high­ly valu­able drugs for his­tor­i­cal­ly hard-to-drug tar­gets.

Septer­na, Inc.’s sci­en­tif­ic founders, Robert Lefkowitz, MD, Arthur Christopolous, PhD, and Patrick Sex­ton, PhD, DSC, are pi­o­neers of GPCR bi­ol­o­gy, as well as world lead­ers in de­vel­op­ing GPCR-tai­lored work­flows to max­i­mize cryo-EM out­put and im­pact. While not re­strict­ed to GPCRs, cryo-EM has rapid­ly ad­vanced since Drs. Jacques Dubo­chet, Joachim Frank, and Richard Hen­der­son were award­ed the 2017 No­bel Prize in Chem­istry for its de­vel­op­ment. The tech­nique has be­come the gold stan­dard method for struc­ture de­ter­mi­na­tion of ac­tive GPCR com­plex­es, and it is now poised to do the same for in­ac­tive-state GPCRs, as well.

Fig­ure 1. Cryo-trans­mis­sion elec­tron mi­cro­scopes (cryo-TEMs), like the Ther­mo Sci­en­tif­ic™ Krios™ G4 Cryo-TEM, bring the ben­e­fits of struc­ture-based drug de­sign to chal­leng­ing tar­gets like glucagon-like pep­tide 1 re­cep­tor (GLP1R). High-res­o­lu­tion cryo-EM mod­el vi­su­al­iz­ing in blue: Pfiz­er’s clin­i­cal-stage GLP1R ag­o­nist danuglipron/PF-06882961 and red: sur­round­ing wa­ter net­work.

A glimpse in­to the ca­pa­bil­i­ties of cryo-EM struc­ture-based drug de­sign and the Septer­na, Inc. team’s in­ti­mate un­der­stand­ing of GPCRs is pro­vid­ed through vi­su­al­iz­ing the mech­a­nism by which al­losteric mod­u­la­tion of adeno­sine A1 re­cep­tor (A1R) can me­di­ate anal­ge­sia in a con­text-spe­cif­ic man­ner.⁴ Al­losteric mod­u­la­tors are lig­ands that bind away from the bind­ing site of na­tive GPCR lig­ands and to pock­ets that can sub­tly tweak a re­cep­tor’s func­tion. This is akin to us­ing a dim­mer switch rather than a strict on/off switch and pro­vides more con­trol over side-ef­fects. Fur­ther­more, al­losteric bind­ing sites are less con­served and bet­ter suit­ed for de­sign­ing re­cep­tor sub­type-spe­cif­ic com­pounds. Drs. Christopolous and Sex­ton used cryo-EM to dis­cov­er an al­losteric bind­ing pock­et of A1R and show that it could be ex­ploit­ed to de­sign non-opi­oid anal­gesics that ex­ert their func­tion in the spinal cord, pro­vid­ing sig­nif­i­cant promise for the treat­ment of neu­ro­path­ic pain.

From cryo-EM-aid­ed to cryo-EM-dri­ven drug de­sign for chem­i­cal di­ver­si­ty and speed

For drug tar­gets with a com­plex bi­ol­o­gy, find­ing the nar­row path to drug de­sign re­quires in­no­v­a­tive chem­istry and re­li­able as­says that are pre­dic­tive for the ther­a­peu­tic hy­poth­e­sis. Cryo-EM plat­form com­pa­nies of­fer the promise of un­prece­dent­ed ac­cess to drug-like chem­i­cal space and com­pressed drug dis­cov­ery time­lines by us­ing in sil­i­co meth­ods as the dri­ving force of com­pound de­sign.

Con­ven­tion­al­ly, phar­ma­ceu­ti­cal com­pa­nies syn­the­size thou­sands of com­pounds per drug dis­cov­ery pro­gram, test­ing their func­tions in bi­o­log­i­cal as­says. How­ev­er, de­vel­op­ing ap­pro­pri­ate as­says can be dif­fi­cult, lengthy, and ex­pen­sive. While struc­ture-based drug de­sign is known to aid the ef­fi­cien­cy of such de­sign-make-test-an­a­lyze (DM­TA) cy­cles, it does not tra­di­tion­al­ly dri­ve small mol­e­cule dis­cov­ery.⁵

Fig­ure 2. The role of struc­ture in drug de­sign is rapid­ly evolv­ing from a sup­port­ing role to the dri­ving force.

In drug de­sign that is dri­ven by cryo-EM struc­ture-based drug de­sign, high-res­o­lu­tion struc­tures of tar­get–lig­and com­plex­es can pro­vide read­outs to fine-tune phar­ma­co­log­i­cal prop­er­ties and re­duce re­liance on bi­o­log­i­cal as­says. A note­wor­thy ex­am­ple is the analy­sis of GLP1R struc­tures, which is a promi­nent GPCR tar­get for di­a­betes and weight loss. For GLP1R, phar­ma­co­log­i­cal end­points cor­re­late with mol­e­c­u­lar de­ter­mi­nants such as crit­i­cal wa­ter net­works or changes in re­cep­tor dy­nam­ics that can be vi­su­al­ized with cryo-EM.^6,7 Fur­ther­more, cryo-EM struc­ture-based drug de­sign is par­tic­u­lar­ly pow­er­ful when in­te­grat­ed with com­pu­ta­tion­al meth­ods that can eval­u­ate bil­lions of drug-like com­pounds per week.⁵ Dra­mat­ic ad­vances in physics-based meth­ods and in the ca­pa­bil­i­ties of ar­ti­fi­cial in­tel­li­gence give cryo-EM struc­ture-based drug de­sign the pow­er to achieve high­ly op­ti­mized drug can­di­dates with far few­er DM­TA cy­cles. In sum­ma­tion, cryo-EM struc­ture-based drug de­sign en­ables com­pa­nies to dis­cov­er bet­ter drugs for im­por­tant dis­eases in less time.

Ther­mo Sci­en­tif­ic™ cryo-EM SB­DD plat­forms and eco-sys­tem of drug tar­get ex­cel­lence

Ther­mo Fish­er Sci­en­tif­ic is the world leader in cryo-EM in­stru­men­ta­tion and is un­ri­valed in un­lock­ing the full po­ten­tial of cryo-EM struc­ture-based drug de­sign for next-gen­er­a­tion small mol­e­cule, pro­tein de­graders, bi­o­log­ics, cell, and gene ther­a­pies. Ther­mo Sci­en­tif­ic cryo-TEMs pro­vide the high­est res­o­lu­tion, struc­ture through­put, and ease-of-use.⁸ The newest in­stru­ments im­ple­ment ar­ti­fi­cial in­tel­li­gence to de­liv­er un­par­al­leled au­toma­tion that pro­vides a strong com­pet­i­tive edge. The com­pa­ny takes own­er­ship of cus­tomer suc­cess, go­ing far be­yond cryo-TEMs to span the en­tire work­flow (http://www.ther­mofish­er.com/phar­madrugdis­cov­ery/), with sig­nif­i­cant gene-to-drug ex­per­tise that can be used by cus­tomers to ac­cel­er­ate their plat­form and ap­pli­ca­tion de­vel­op­ment. Last­ly, the com­pa­ny has an ex­ten­sive net­work of key opin­ion lead­ers in pro­tein sci­ence who bring ex­pert un­der­stand­ing of high­ly com­plex drug tar­get class­es and are a hotbed for the in­cep­tion of new ther­a­peu­tic op­por­tu­ni­ties.

Fig­ure 3. Based on our ex­ten­sive ex­per­tise in help­ing cus­tomers de­vel­op cryo-EM dis­cov­ery plat­forms, Ther­mo Sci­en­tif­ic cryo-TEMs can help ac­cel­er­ate the dis­cov­ery of med­i­cines for the most im­por­tant dis­eases. Ap­pli­ca­tions range from mem­brane pro­teins to epi­tope map­ping, vac­cines, de­graders, chimeric anti­gen re­cep­tor T (CAR T) cells, off-tar­get ef­fects and more.

Tak­en to­geth­er, this in­ter­sec­tion of trans­for­ma­tive struc­ture-based drug de­sign tech­nolo­gies and drug tar­get ex­cel­lence pro­vides fer­tile grounds for bet­ter med­i­cines that ven­ture cap­i­tal­ist firms like Third Rock Ven­tures are bet­ting on. Com­pa­nies like Septer­na, Inc., Ther­a­peu­tics may be the pre­cur­sors of a big­ger cryo-EM start­up wave.

For re­search use on­ly. Not for use in di­ag­nos­tic pro­ce­dures. For cur­rent cer­ti­fi­ca­tions, vis­it ther­mofish­er.com/cer­ti­fi­ca­tions © 2022 Ther­mo Fish­er Sci­en­tif­ic Inc. All rights re­served. All trade­marks are the prop­er­ty of Ther­mo Fish­er Sci­en­tif­ic and its sub­sidiaries un­less oth­er­wise spec­i­fied.

Ref­er­ences:

1. Wigge C, Ste­fanovic A, Rad­jainia M. (2020) The rapid­ly evolv­ing role of cryo-EM in drug de­sign. Drug Dis­cov To­day Tech­nol 38:91–102.
2. Con­greve M, de Graaf C, Swain NA, Tate CG. (2020) Im­pact of GPCR struc­tures on drug dis­cov­ery. Cell 181(1):81–91.
3. Brown AJH, Bradley SJ, Mar­shall FH et al. (2021) From struc­ture to clin­ic: De­sign of a mus­carinic M1 re­cep­tor ag­o­nist with po­ten­tial to treat­ment of Alzheimer’s dis­ease. Cell 184(24):5886–5901.e22.
4. Drap­er-Joyce CJ, Bho­la R, Wang J et al. (2021) Pos­i­tive al­losteric mech­a­nisms of adeno­sine A1 re­cep­tor-me­di­at­ed anal­ge­sia. Na­ture 597(7877):571–576. doi: 10.1038/s41586-021-03897-2. Epub 2021 Sep 8.
5. Frye L, Bhat S, Akin­sanya K, Abel R. (2021) From com­put­er-aid­ed drug dis­cov­ery to com­put­er-dri­ven drug dis­cov­ery. Drug Dis­cov To­day Tech­nol 39:111–117.
6. Zhang X, Be­lousoff MJ, Zhao P et al. (2020) Dif­fer­en­tial GLP-1R bind­ing and ac­ti­va­tion by pep­tide and non-pep­tide ag­o­nists. Mol Cell 80(3):485–500.e7.
7. Zhang X, Be­lousoff MJ, Liang YL et al. (2021) Struc­ture and dy­nam­ics of semaglu­tide- and tas­pog­lu­tide-bound GLP-1R-Gs com­plex­es. Cell Rep 2021 36(2):109374.
8. Nakane T, Kotecha A, Sente A et al. (2020) Sin­gle-par­ti­cle cryo-EM at atom­ic res­o­lu­tion. Na­ture 587(7832):152–156.