{"id":"https://openalex.org/W4408403120","doi":"https://doi.org/10.1101/2025.03.07.642093","title":"Nanobody-based conjugates targeting small molecule-binding GPCRs and exhibiting logic-gated signaling","display_name":"Nanobody-based conjugates targeting small molecule-binding GPCRs and exhibiting logic-gated signaling","publication_year":2025,"publication_date":"2025-03-12","ids":{"openalex":"https://openalex.org/W4408403120","doi":"https://doi.org/10.1101/2025.03.07.642093","pmid":"https://pubmed.ncbi.nlm.nih.gov/41031018","pmcid":"https://www.ncbi.nlm.nih.gov/pmc/articles/12478371"},"language":"en","primary_location":{"id":"doi:10.1101/2025.03.07.642093","doi":"https://doi.org/10.1101/2025.03.07.642093","is_oa":true,"landing_page_url":"https://doi.org/10.1101/2025.03.07.642093","pdf_url":null,"source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"public-domain","license_id":"https://openalex.org/licenses/public-domain","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"volume":null,"type":"preprint","indexed_in":["crossref","pubmed"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://doi.org/10.1101/2025.03.07.642093","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5027767206","display_name":"Shivani Sachdev","orcid":"https://orcid.org/0000-0003-2514-9189","observed_orcids":["https://orcid.org/0000-0003-2514-9189"]},"institutions":[{"id":"https://openalex.org/I1299303238","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88","country_code":"US","type":"government","lineage":["https://openalex.org/I1299022934","https://openalex.org/I1299303238"]},{"id":"https://openalex.org/I4210090567","display_name":"National Institute of Diabetes and Digestive and Kidney Diseases","ror":"https://ror.org/00adh9b73","country_code":"US","type":"facility","lineage":["https://openalex.org/I1299022934","https://openalex.org/I1299303238","https://openalex.org/I4210090567"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Shivani Sachdev","raw_affiliation_strings":["Laboratory of Bioorganic Chemistry; National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health, USA","National Institutes of Health Intramural Research Program"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Laboratory of Bioorganic Chemistry; National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health, USA","institution_ids":["https://openalex.org/I1299303238","https://openalex.org/I4210090567"]},{"raw_affiliation_string":"National Institutes of Health Intramural Research Program","institution_ids":["https://openalex.org/I1299303238"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5100620321","display_name":"Swarnali Roy","orcid":"https://orcid.org/0009-0006-7449-6776","observed_orcids":["https://orcid.org/0009-0006-7449-6776"]},"institutions":[{"id":"https://openalex.org/I1299303238","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88","country_code":"US","type":"government","lineage":["https://openalex.org/I1299022934","https://openalex.org/I1299303238"]},{"id":"https://openalex.org/I4210090567","display_name":"National Institute of Diabetes and Digestive and Kidney Diseases","ror":"https://ror.org/00adh9b73","country_code":"US","type":"facility","lineage":["https://openalex.org/I1299022934","https://openalex.org/I1299303238","https://openalex.org/I4210090567"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Swarnali Roy","raw_affiliation_strings":["Laboratory of Bioorganic Chemistry; National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health, USA","National Institutes of Health Intramural Research Program"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Laboratory of Bioorganic Chemistry; National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health, USA","institution_ids":["https://openalex.org/I1299303238","https://openalex.org/I4210090567"]},{"raw_affiliation_string":"National Institutes of Health Intramural Research Program","institution_ids":["https://openalex.org/I1299303238"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5018356508","display_name":"Ross W. Cheloha","orcid":"https://orcid.org/0000-0001-9871-8333","observed_orcids":["https://orcid.org/0000-0001-9871-8333"]},"institutions":[{"id":"https://openalex.org/I1299303238","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88","country_code":"US","type":"government","lineage":["https://openalex.org/I1299022934","https://openalex.org/I1299303238"]},{"id":"https://openalex.org/I4210090567","display_name":"National Institute of Diabetes and Digestive and Kidney Diseases","ror":"https://ror.org/00adh9b73","country_code":"US","type":"facility","lineage":["https://openalex.org/I1299022934","https://openalex.org/I1299303238","https://openalex.org/I4210090567"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Ross W. Cheloha","raw_affiliation_strings":["Laboratory of Bioorganic Chemistry; National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Laboratory of Bioorganic Chemistry; National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health, USA","institution_ids":["https://openalex.org/I1299303238","https://openalex.org/I4210090567"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":2,"corresponding_author_ids":["https://openalex.org/A5018356508"],"corresponding_institution_ids":["https://openalex.org/I1299303238","https://openalex.org/I4210090567"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":1,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11178","display_name":"Receptor Mechanisms and Signaling","score":0.9984999895095825,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T11178","display_name":"Receptor Mechanisms and Signaling","score":0.9984999895095825,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11193","display_name":"Adenosine and Purinergic Signaling","score":0.0003000000142492354,"subfield":{"id":"https://openalex.org/subfields/1314","display_name":"Physiology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11016","display_name":"Monoclonal and Polyclonal Antibodies Research","score":9.999999747378752e-05,"subfield":{"id":"https://openalex.org/subfields/2741","display_name":"Radiology, Nuclear Medicine and Imaging"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/bitopic-ligands","display_name":"bitopic ligands","score":0.8669999837875366},{"id":"https://openalex.org/keywords/g-protein-coupled-receptors","display_name":"G protein-coupled receptors","score":0.972000002861023},{"id":"https://openalex.org/keywords/adenosine-a2a-receptor","display_name":"adenosine A2A receptor","score":0.9919999837875366},{"id":"https://openalex.org/keywords/receptor-dimerization","display_name":"receptor dimerization","score":0.6779999732971191},{"id":"https://openalex.org/keywords/dual-targeting","display_name":"dual targeting","score":0.5609999895095825},{"id":"https://openalex.org/keywords/gpcr-drug-discovery","display_name":"GPCR drug discovery","score":0.8519999980926514}],"concepts":[{"id":"https://openalex.org/C197336794","wikidata":"https://www.wikidata.org/wiki/Q5161150","display_name":"Conjugate","level":2,"score":0.6757240891456604},{"id":"https://openalex.org/C135285700","wikidata":"https://www.wikidata.org/wiki/Q38173","display_name":"G protein-coupled receptor","level":3,"score":0.6208748817443848},{"id":"https://openalex.org/C161624437","wikidata":"https://www.wikidata.org/wiki/Q1988322","display_name":"Small molecule","level":2,"score":0.5614022016525269},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.5001084804534912},{"id":"https://openalex.org/C150555746","wikidata":"https://www.wikidata.org/wiki/Q210973","display_name":"Cell signaling","level":3,"score":0.4124520421028137},{"id":"https://openalex.org/C170493617","wikidata":"https://www.wikidata.org/wiki/Q208467","display_name":"Receptor","level":2,"score":0.4086366891860962},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.3885441720485687},{"id":"https://openalex.org/C62478195","wikidata":"https://www.wikidata.org/wiki/Q828130","display_name":"Signal transduction","level":2,"score":0.3492548167705536},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.33933335542678833},{"id":"https://openalex.org/C171250308","wikidata":"https://www.wikidata.org/wiki/Q11468","display_name":"Nanotechnology","level":1,"score":0.33704113960266113},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.22800102829933167},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.2277701199054718},{"id":"https://openalex.org/C192562407","wikidata":"https://www.wikidata.org/wiki/Q228736","display_name":"Materials science","level":0,"score":0.15952184796333313},{"id":"https://openalex.org/C33923547","wikidata":"https://www.wikidata.org/wiki/Q395","display_name":"Mathematics","level":0,"score":0.08062049746513367},{"id":"https://openalex.org/C134306372","wikidata":"https://www.wikidata.org/wiki/Q7754","display_name":"Mathematical analysis","level":1,"score":0.0}],"mesh":[],"locations_count":4,"locations":[{"id":"doi:10.1101/2025.03.07.642093","doi":"https://doi.org/10.1101/2025.03.07.642093","is_oa":true,"landing_page_url":"https://doi.org/10.1101/2025.03.07.642093","pdf_url":null,"source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"public-domain","license_id":"https://openalex.org/licenses/public-domain","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},{"id":"pmid:41031018","doi":null,"is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/41031018","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"bioRxiv : the preprint server for biology","raw_type":"Journal Article"},{"id":"pmh:oai:pubmedcentral.nih.gov:12478371","doi":null,"is_oa":true,"landing_page_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12478371/","pdf_url":null,"source":{"id":"https://openalex.org/S2764455111","display_name":"PubMed Central","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":"public-domain","license_id":"https://openalex.org/licenses/public-domain","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"bioRxiv","raw_type":"Text"},{"id":"pmh:oai:europepmc.org:11289090","doi":null,"is_oa":true,"landing_page_url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12478371","pdf_url":null,"source":{"id":"https://openalex.org/S4306400806","display_name":"Europe PMC (PubMed Central)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1303153112","host_organization_name":"European Bioinformatics Institute","host_organization_lineage":["https://openalex.org/I1303153112"],"host_organization_lineage_names":[],"type":"repository"},"license":"public-domain","license_id":"https://openalex.org/licenses/public-domain","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"Text"}],"best_oa_location":{"id":"doi:10.1101/2025.03.07.642093","doi":"https://doi.org/10.1101/2025.03.07.642093","is_oa":true,"landing_page_url":"https://doi.org/10.1101/2025.03.07.642093","pdf_url":null,"source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"public-domain","license_id":"https://openalex.org/licenses/public-domain","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"sustainable_development_goals":[{"score":0.4043000042438507,"display_name":"Good health and well-being","id":"https://metadata.un.org/sdg/3"}],"study_designs":[],"awards":[{"id":"https://openalex.org/G9000896420","display_name":"New tools from chemistry and antibodies to address receptor function","funder_award_id":"ZIADK075157","funder_id":"https://openalex.org/F4320337357","funder_display_name":"National Institute of Diabetes and Digestive and Kidney Diseases"}],"funders":[{"id":"https://openalex.org/F4320337357","display_name":"National Institute of Diabetes and Digestive and Kidney Diseases","ror":"https://ror.org/00adh9b73"}],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":53,"referenced_works":["https://openalex.org/W1986682556","https://openalex.org/W2040166532","https://openalex.org/W2048553889","https://openalex.org/W2050555151","https://openalex.org/W2079576324","https://openalex.org/W2089788910","https://openalex.org/W2121443918","https://openalex.org/W2221707331","https://openalex.org/W2258399945","https://openalex.org/W2333223032","https://openalex.org/W2412092132","https://openalex.org/W2548166139","https://openalex.org/W2786832567","https://openalex.org/W2795481136","https://openalex.org/W2911446286","https://openalex.org/W2928555551","https://openalex.org/W2972952141","https://openalex.org/W2973145235","https://openalex.org/W2976500897","https://openalex.org/W2996405687","https://openalex.org/W3000738780","https://openalex.org/W3014096229","https://openalex.org/W3014461065","https://openalex.org/W3022812876","https://openalex.org/W3022893071","https://openalex.org/W3025464445","https://openalex.org/W3081642245","https://openalex.org/W3129083073","https://openalex.org/W3179257742","https://openalex.org/W3205837077","https://openalex.org/W3208960287","https://openalex.org/W4220763721","https://openalex.org/W4281790889","https://openalex.org/W4287509974","https://openalex.org/W4289953209","https://openalex.org/W4293553619","https://openalex.org/W4293770211","https://openalex.org/W4295903777","https://openalex.org/W4311679232","https://openalex.org/W4324348065","https://openalex.org/W4361276410","https://openalex.org/W4382049661","https://openalex.org/W4389675501","https://openalex.org/W4390062814","https://openalex.org/W4392947112","https://openalex.org/W4394623467","https://openalex.org/W4399173171","https://openalex.org/W4399257513","https://openalex.org/W4401352275","https://openalex.org/W4403039472","https://openalex.org/W4403253406","https://openalex.org/W4404679119","https://openalex.org/W4405056347"],"related_works":["https://openalex.org/W4416572730","https://openalex.org/W4416510677","https://openalex.org/W4396850130","https://openalex.org/W4396849605","https://openalex.org/W7160879836","https://openalex.org/W4389675501","https://openalex.org/W7162990290","https://openalex.org/W2022565123","https://openalex.org/W2996619659","https://openalex.org/W4286247371"],"abstract_inverted_index":{"G":[0],"protein-coupled":[1],"receptors":[2,15],"(GPCRs)":[3],"are":[4,16,36],"the":[5,43,67,83,97,143,161],"largest":[6],"family":[7],"of":[8,22,38,71,76,103,146,156,164,178],"plasma":[9],"membrane":[10],"embedded":[11],"signaling":[12,122,195,223],"proteins.":[13],"These":[14],"involved":[17],"in":[18,167,174],"a":[19,39,48,54,77,154,215],"wide":[20],"array":[21],"physiological":[23],"processes,":[24],"marking":[25],"them":[26],"as":[27,153],"attractive":[28],"targets":[29,42],"for":[30,60,220,226],"drug":[31,228],"development.":[32],"Bitopic":[33],"ligands,":[34],"which":[35],"comprised":[37],"pharmacophore":[40,80],"that":[41,51,81,117,127,190,197],"receptor":[44,86,138,147,209],"orthosteric":[45],"site":[46],"and":[47,69,100,120,224],"linked":[49,88],"moiety":[50],"binds":[52],"to":[53,89,105,112,207],"separate":[55],"site,":[56],"have":[57],"considerable":[58],"potential":[59,219],"addressing":[61],"GPCR":[62,182,227],"function.":[63],"Here,":[64],"we":[65,188],"report":[66],"synthesis":[68],"evaluation":[70],"novel":[72],"bitopic":[73,114,129,165],"conjugates":[74,116,130,166,213],"consisting":[75],"small":[78],"molecule":[79],"activates":[82],"adenosine":[84],"A2A":[85],"(A2AR)":[87],"antibody":[90],"fragments":[91],"(nanobodies,":[92],"Nbs).":[93],"This":[94,140],"approach":[95],"leverages":[96],"high":[98],"affinity":[99],"specificity":[101],"binding":[102],"Nbs":[104],"non-orthosteric":[106],"sites":[107],"on":[108],"engineered":[109],"A2AR":[110],"variants":[111],"provide":[113],"Nb-ligand":[115],"stimulate":[118],"strong":[119],"enduring":[121],"responses.":[123],"We":[124,159],"further":[125],"demonstrate":[126,189],"such":[128],"can":[131],"induce":[132],"activation":[133],"by":[134,170,202],"spanning":[135],"two":[136],"distinct":[137],"protomers.":[139],"property":[141],"enables":[142],"selective":[144],"targeting":[145,175],"pairs":[148,177,210],"over":[149],"either":[150],"individual":[151],"receptor,":[152],"form":[155],"\"logic-gated\"":[157],"activity.":[158],"showcase":[160],"broad":[162],"applicability":[163],"this":[168,191],"context":[169],"demonstrating":[171],"their":[172],"activity":[173],"several":[176],"co-expressed":[179],"receptors,":[180],"including":[181],"monomers":[183],"from":[184,199],"different":[185],"classes.":[186],"Furthermore,":[187],"dual-targeting":[192],"strategy":[193,217],"initiates":[194],"responses":[196],"diverge":[198],"those":[200],"induced":[201],"monovalent":[203],"ligands.":[204],"The":[205],"ability":[206],"target":[208],"using":[211],"nanobody-ligand":[212],"offers":[214],"powerful":[216],"with":[218],"cell":[221],"type-selective":[222],"implications":[225],"discovery":[229],"efforts":[230],"more":[231],"broadly.":[232]},"counts_by_year":[{"year":2026,"cited_by_count":1}],"updated_date":"2026-10-28T10:33:24.094632","created_date":"2025-03-14T00:00:00"}
